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Publisher: Elsevier   (Total: 3157 journals)

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Showing 1 - 200 of 3160 Journals sorted alphabetically
A Practical Logic of Cognitive Systems     Full-text available via subscription   (Followers: 9)
AASRI Procedia     Open Access   (Followers: 15)
Academic Pediatrics     Hybrid Journal   (Followers: 35, SJR: 1.655, CiteScore: 2)
Academic Radiology     Hybrid Journal   (Followers: 24, SJR: 1.015, CiteScore: 2)
Accident Analysis & Prevention     Partially Free   (Followers: 96, SJR: 1.462, CiteScore: 3)
Accounting Forum     Hybrid Journal   (Followers: 27, SJR: 0.932, CiteScore: 2)
Accounting, Organizations and Society     Hybrid Journal   (Followers: 37, SJR: 1.771, CiteScore: 3)
Achievements in the Life Sciences     Open Access   (Followers: 5)
Acta Anaesthesiologica Taiwanica     Open Access   (Followers: 7)
Acta Astronautica     Hybrid Journal   (Followers: 417, SJR: 0.758, CiteScore: 2)
Acta Automatica Sinica     Full-text available via subscription   (Followers: 2)
Acta Biomaterialia     Hybrid Journal   (Followers: 27, SJR: 1.967, CiteScore: 7)
Acta Colombiana de Cuidado Intensivo     Full-text available via subscription   (Followers: 2)
Acta de Investigación Psicológica     Open Access   (Followers: 3)
Acta Ecologica Sinica     Open Access   (Followers: 10, SJR: 0.18, CiteScore: 1)
Acta Haematologica Polonica     Free   (Followers: 1, SJR: 0.128, CiteScore: 0)
Acta Histochemica     Hybrid Journal   (Followers: 3, SJR: 0.661, CiteScore: 2)
Acta Materialia     Hybrid Journal   (Followers: 262, SJR: 3.263, CiteScore: 6)
Acta Mathematica Scientia     Full-text available via subscription   (Followers: 5, SJR: 0.504, CiteScore: 1)
Acta Mechanica Solida Sinica     Full-text available via subscription   (Followers: 9, SJR: 0.542, CiteScore: 1)
Acta Oecologica     Hybrid Journal   (Followers: 12, SJR: 0.834, CiteScore: 2)
Acta Otorrinolaringologica (English Edition)     Full-text available via subscription  
Acta Otorrinolaringológica Española     Full-text available via subscription   (Followers: 3, SJR: 0.307, CiteScore: 0)
Acta Pharmaceutica Sinica B     Open Access   (Followers: 1, SJR: 1.793, CiteScore: 6)
Acta Poética     Open Access   (Followers: 4, SJR: 0.101, CiteScore: 0)
Acta Psychologica     Hybrid Journal   (Followers: 27, SJR: 1.331, CiteScore: 2)
Acta Sociológica     Open Access   (Followers: 1)
Acta Tropica     Hybrid Journal   (Followers: 6, SJR: 1.052, CiteScore: 2)
Acta Urológica Portuguesa     Open Access  
Actas Dermo-Sifiliograficas     Full-text available via subscription   (Followers: 3, SJR: 0.374, CiteScore: 1)
Actas Dermo-Sifiliográficas (English Edition)     Full-text available via subscription   (Followers: 2)
Actas Urológicas Españolas     Full-text available via subscription   (Followers: 3, SJR: 0.344, CiteScore: 1)
Actas Urológicas Españolas (English Edition)     Full-text available via subscription   (Followers: 1)
Actualites Pharmaceutiques     Full-text available via subscription   (Followers: 6, SJR: 0.19, CiteScore: 0)
Actualites Pharmaceutiques Hospitalieres     Full-text available via subscription   (Followers: 3)
Acupuncture and Related Therapies     Hybrid Journal   (Followers: 7)
Acute Pain     Full-text available via subscription   (Followers: 14, SJR: 2.671, CiteScore: 5)
Ad Hoc Networks     Hybrid Journal   (Followers: 11, SJR: 0.53, CiteScore: 4)
Addictive Behaviors     Hybrid Journal   (Followers: 17, SJR: 1.29, CiteScore: 3)
Addictive Behaviors Reports     Open Access   (Followers: 8, SJR: 0.755, CiteScore: 2)
Additive Manufacturing     Hybrid Journal   (Followers: 10, SJR: 2.611, CiteScore: 8)
Additives for Polymers     Full-text available via subscription   (Followers: 23)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 160, SJR: 4.09, CiteScore: 13)
Advanced Engineering Informatics     Hybrid Journal   (Followers: 11, SJR: 1.167, CiteScore: 4)
Advanced Powder Technology     Hybrid Journal   (Followers: 17, SJR: 0.694, CiteScore: 3)
Advances in Accounting     Hybrid Journal   (Followers: 8, SJR: 0.277, CiteScore: 1)
Advances in Agronomy     Full-text available via subscription   (Followers: 15, SJR: 2.384, CiteScore: 5)
Advances in Anesthesia     Full-text available via subscription   (Followers: 28, SJR: 0.126, CiteScore: 0)
Advances in Antiviral Drug Design     Full-text available via subscription   (Followers: 2)
Advances in Applied Mathematics     Full-text available via subscription   (Followers: 10, SJR: 0.992, CiteScore: 1)
Advances in Applied Mechanics     Full-text available via subscription   (Followers: 11, SJR: 1.551, CiteScore: 4)
Advances in Applied Microbiology     Full-text available via subscription   (Followers: 24, SJR: 2.089, CiteScore: 5)
Advances In Atomic, Molecular, and Optical Physics     Full-text available via subscription   (Followers: 14, SJR: 0.572, CiteScore: 2)
Advances in Biological Regulation     Hybrid Journal   (Followers: 4, SJR: 2.61, CiteScore: 7)
Advances in Botanical Research     Full-text available via subscription   (Followers: 2, SJR: 0.686, CiteScore: 2)
Advances in Cancer Research     Full-text available via subscription   (Followers: 33, SJR: 3.043, CiteScore: 6)
Advances in Carbohydrate Chemistry and Biochemistry     Full-text available via subscription   (Followers: 9, SJR: 1.453, CiteScore: 2)
Advances in Catalysis     Full-text available via subscription   (Followers: 5, SJR: 1.992, CiteScore: 5)
Advances in Cell Aging and Gerontology     Full-text available via subscription   (Followers: 4)
Advances in Cellular and Molecular Biology of Membranes and Organelles     Full-text available via subscription   (Followers: 12)
Advances in Chemical Engineering     Full-text available via subscription   (Followers: 27, SJR: 0.156, CiteScore: 1)
Advances in Child Development and Behavior     Full-text available via subscription   (Followers: 10, SJR: 0.713, CiteScore: 1)
Advances in Chronic Kidney Disease     Full-text available via subscription   (Followers: 9, SJR: 1.316, CiteScore: 2)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26, SJR: 1.562, CiteScore: 3)
Advances in Colloid and Interface Science     Full-text available via subscription   (Followers: 19, SJR: 1.977, CiteScore: 8)
Advances in Computers     Full-text available via subscription   (Followers: 14, SJR: 0.205, CiteScore: 1)
Advances in Dermatology     Full-text available via subscription   (Followers: 15)
Advances in Developmental Biology     Full-text available via subscription   (Followers: 12)
Advances in Digestive Medicine     Open Access   (Followers: 9)
Advances in DNA Sequence-Specific Agents     Full-text available via subscription   (Followers: 5)
Advances in Drug Research     Full-text available via subscription   (Followers: 25)
Advances in Ecological Research     Full-text available via subscription   (Followers: 44, SJR: 2.524, CiteScore: 4)
Advances in Engineering Software     Hybrid Journal   (Followers: 28, SJR: 1.159, CiteScore: 4)
Advances in Experimental Biology     Full-text available via subscription   (Followers: 8)
Advances in Experimental Social Psychology     Full-text available via subscription   (Followers: 46, SJR: 5.39, CiteScore: 8)
Advances in Exploration Geophysics     Full-text available via subscription   (Followers: 1)
Advances in Fluorine Science     Full-text available via subscription   (Followers: 9)
Advances in Food and Nutrition Research     Full-text available via subscription   (Followers: 59, SJR: 0.591, CiteScore: 2)
Advances in Fuel Cells     Full-text available via subscription   (Followers: 16)
Advances in Genetics     Full-text available via subscription   (Followers: 16, SJR: 1.354, CiteScore: 4)
Advances in Genome Biology     Full-text available via subscription   (Followers: 8, SJR: 12.74, CiteScore: 13)
Advances in Geophysics     Full-text available via subscription   (Followers: 6, SJR: 1.193, CiteScore: 3)
Advances in Heat Transfer     Full-text available via subscription   (Followers: 23, SJR: 0.368, CiteScore: 1)
Advances in Heterocyclic Chemistry     Full-text available via subscription   (Followers: 12, SJR: 0.749, CiteScore: 3)
Advances in Human Factors/Ergonomics     Full-text available via subscription   (Followers: 23)
Advances in Imaging and Electron Physics     Full-text available via subscription   (Followers: 2, SJR: 0.193, CiteScore: 0)
Advances in Immunology     Full-text available via subscription   (Followers: 36, SJR: 4.433, CiteScore: 6)
Advances in Inorganic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 1.163, CiteScore: 2)
Advances in Insect Physiology     Full-text available via subscription   (Followers: 2, SJR: 1.938, CiteScore: 3)
Advances in Integrative Medicine     Hybrid Journal   (Followers: 6, SJR: 0.176, CiteScore: 0)
Advances in Intl. Accounting     Full-text available via subscription   (Followers: 3)
Advances in Life Course Research     Hybrid Journal   (Followers: 8, SJR: 0.682, CiteScore: 2)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Magnetic and Optical Resonance     Full-text available via subscription   (Followers: 8)
Advances in Marine Biology     Full-text available via subscription   (Followers: 18, SJR: 0.88, CiteScore: 2)
Advances in Mathematics     Full-text available via subscription   (Followers: 11, SJR: 3.027, CiteScore: 2)
Advances in Medical Sciences     Hybrid Journal   (Followers: 7, SJR: 0.694, CiteScore: 2)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4, SJR: 1.158, CiteScore: 3)
Advances in Molecular and Cell Biology     Full-text available via subscription   (Followers: 23)
Advances in Molecular and Cellular Endocrinology     Full-text available via subscription   (Followers: 8)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7, SJR: 0.182, CiteScore: 0)
Advances in Nanoporous Materials     Full-text available via subscription   (Followers: 3)
Advances in Oncobiology     Full-text available via subscription   (Followers: 2)
Advances in Organ Biology     Full-text available via subscription   (Followers: 1)
Advances in Organometallic Chemistry     Full-text available via subscription   (Followers: 17, SJR: 1.875, CiteScore: 4)
Advances in Parallel Computing     Full-text available via subscription   (Followers: 7, SJR: 0.174, CiteScore: 0)
Advances in Parasitology     Full-text available via subscription   (Followers: 5, SJR: 1.579, CiteScore: 4)
Advances in Pediatrics     Full-text available via subscription   (Followers: 24, SJR: 0.461, CiteScore: 1)
Advances in Pharmaceutical Sciences     Full-text available via subscription   (Followers: 12)
Advances in Pharmacology     Full-text available via subscription   (Followers: 16, SJR: 1.536, CiteScore: 3)
Advances in Physical Organic Chemistry     Full-text available via subscription   (Followers: 8, SJR: 0.574, CiteScore: 1)
Advances in Phytomedicine     Full-text available via subscription  
Advances in Planar Lipid Bilayers and Liposomes     Full-text available via subscription   (Followers: 3, SJR: 0.109, CiteScore: 1)
Advances in Plant Biochemistry and Molecular Biology     Full-text available via subscription   (Followers: 10)
Advances in Plant Pathology     Full-text available via subscription   (Followers: 5)
Advances in Porous Media     Full-text available via subscription   (Followers: 5)
Advances in Protein Chemistry     Full-text available via subscription   (Followers: 19)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20, SJR: 0.791, CiteScore: 2)
Advances in Psychology     Full-text available via subscription   (Followers: 64)
Advances in Quantum Chemistry     Full-text available via subscription   (Followers: 6, SJR: 0.371, CiteScore: 1)
Advances in Radiation Oncology     Open Access   (SJR: 0.263, CiteScore: 1)
Advances in Small Animal Medicine and Surgery     Hybrid Journal   (Followers: 3, SJR: 0.101, CiteScore: 0)
Advances in Space Biology and Medicine     Full-text available via subscription   (Followers: 6)
Advances in Space Research     Full-text available via subscription   (Followers: 404, SJR: 0.569, CiteScore: 2)
Advances in Structural Biology     Full-text available via subscription   (Followers: 5)
Advances in Surgery     Full-text available via subscription   (Followers: 11, SJR: 0.555, CiteScore: 2)
Advances in the Study of Behavior     Full-text available via subscription   (Followers: 34, SJR: 2.208, CiteScore: 4)
Advances in Veterinary Medicine     Full-text available via subscription   (Followers: 18)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 14)
Advances in Virus Research     Full-text available via subscription   (Followers: 5, SJR: 2.262, CiteScore: 5)
Advances in Water Resources     Hybrid Journal   (Followers: 47, SJR: 1.551, CiteScore: 3)
Aeolian Research     Hybrid Journal   (Followers: 6, SJR: 1.117, CiteScore: 3)
Aerospace Science and Technology     Hybrid Journal   (Followers: 352, SJR: 0.796, CiteScore: 3)
AEU - Intl. J. of Electronics and Communications     Hybrid Journal   (Followers: 8, SJR: 0.42, CiteScore: 2)
African J. of Emergency Medicine     Open Access   (Followers: 6, SJR: 0.296, CiteScore: 0)
Ageing Research Reviews     Hybrid Journal   (Followers: 11, SJR: 3.671, CiteScore: 9)
Aggression and Violent Behavior     Hybrid Journal   (Followers: 457, SJR: 1.238, CiteScore: 3)
Agri Gene     Hybrid Journal   (Followers: 1, SJR: 0.13, CiteScore: 0)
Agricultural and Forest Meteorology     Hybrid Journal   (Followers: 17, SJR: 1.818, CiteScore: 5)
Agricultural Systems     Hybrid Journal   (Followers: 31, SJR: 1.156, CiteScore: 4)
Agricultural Water Management     Hybrid Journal   (Followers: 42, SJR: 1.272, CiteScore: 3)
Agriculture and Agricultural Science Procedia     Open Access   (Followers: 4)
Agriculture and Natural Resources     Open Access   (Followers: 3)
Agriculture, Ecosystems & Environment     Hybrid Journal   (Followers: 57, SJR: 1.747, CiteScore: 4)
Ain Shams Engineering J.     Open Access   (Followers: 5, SJR: 0.589, CiteScore: 3)
Air Medical J.     Hybrid Journal   (Followers: 6, SJR: 0.26, CiteScore: 0)
AKCE Intl. J. of Graphs and Combinatorics     Open Access   (SJR: 0.19, CiteScore: 0)
Alcohol     Hybrid Journal   (Followers: 12, SJR: 1.153, CiteScore: 3)
Alcoholism and Drug Addiction     Open Access   (Followers: 11)
Alergologia Polska : Polish J. of Allergology     Full-text available via subscription   (Followers: 1)
Alexandria Engineering J.     Open Access   (Followers: 1, SJR: 0.604, CiteScore: 3)
Alexandria J. of Medicine     Open Access   (Followers: 1, SJR: 0.191, CiteScore: 1)
Algal Research     Partially Free   (Followers: 10, SJR: 1.142, CiteScore: 4)
Alkaloids: Chemical and Biological Perspectives     Full-text available via subscription   (Followers: 2)
Allergologia et Immunopathologia     Full-text available via subscription   (Followers: 1, SJR: 0.504, CiteScore: 1)
Allergology Intl.     Open Access   (Followers: 5, SJR: 1.148, CiteScore: 2)
Alpha Omegan     Full-text available via subscription   (SJR: 3.521, CiteScore: 6)
ALTER - European J. of Disability Research / Revue Européenne de Recherche sur le Handicap     Full-text available via subscription   (Followers: 10, SJR: 0.201, CiteScore: 1)
Alzheimer's & Dementia     Hybrid Journal   (Followers: 51, SJR: 4.66, CiteScore: 10)
Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring     Open Access   (Followers: 4, SJR: 1.796, CiteScore: 4)
Alzheimer's & Dementia: Translational Research & Clinical Interventions     Open Access   (Followers: 4, SJR: 1.108, CiteScore: 3)
Ambulatory Pediatrics     Hybrid Journal   (Followers: 6)
American Heart J.     Hybrid Journal   (Followers: 53, SJR: 3.267, CiteScore: 4)
American J. of Cardiology     Hybrid Journal   (Followers: 56, SJR: 1.93, CiteScore: 3)
American J. of Emergency Medicine     Hybrid Journal   (Followers: 44, SJR: 0.604, CiteScore: 1)
American J. of Geriatric Pharmacotherapy     Full-text available via subscription   (Followers: 10)
American J. of Geriatric Psychiatry     Hybrid Journal   (Followers: 14, SJR: 1.524, CiteScore: 3)
American J. of Human Genetics     Hybrid Journal   (Followers: 34, SJR: 7.45, CiteScore: 8)
American J. of Infection Control     Hybrid Journal   (Followers: 29, SJR: 1.062, CiteScore: 2)
American J. of Kidney Diseases     Hybrid Journal   (Followers: 35, SJR: 2.973, CiteScore: 4)
American J. of Medicine     Hybrid Journal   (Followers: 47)
American J. of Medicine Supplements     Full-text available via subscription   (Followers: 3, SJR: 1.967, CiteScore: 2)
American J. of Obstetrics and Gynecology     Hybrid Journal   (Followers: 223, SJR: 2.7, CiteScore: 4)
American J. of Ophthalmology     Hybrid Journal   (Followers: 66, SJR: 3.184, CiteScore: 4)
American J. of Ophthalmology Case Reports     Open Access   (Followers: 5, SJR: 0.265, CiteScore: 0)
American J. of Orthodontics and Dentofacial Orthopedics     Full-text available via subscription   (Followers: 6, SJR: 1.289, CiteScore: 1)
American J. of Otolaryngology     Hybrid Journal   (Followers: 25, SJR: 0.59, CiteScore: 1)
American J. of Pathology     Hybrid Journal   (Followers: 28, SJR: 2.139, CiteScore: 4)
American J. of Preventive Medicine     Hybrid Journal   (Followers: 28, SJR: 2.164, CiteScore: 4)
American J. of Surgery     Hybrid Journal   (Followers: 38, SJR: 1.141, CiteScore: 2)
American J. of the Medical Sciences     Hybrid Journal   (Followers: 12, SJR: 0.767, CiteScore: 1)
Ampersand : An Intl. J. of General and Applied Linguistics     Open Access   (Followers: 7)
Anaerobe     Hybrid Journal   (Followers: 4, SJR: 1.144, CiteScore: 3)
Anaesthesia & Intensive Care Medicine     Full-text available via subscription   (Followers: 63, SJR: 0.138, CiteScore: 0)
Anaesthesia Critical Care & Pain Medicine     Full-text available via subscription   (Followers: 18, SJR: 0.411, CiteScore: 1)
Anales de Cirugia Vascular     Full-text available via subscription  
Anales de Pediatría     Full-text available via subscription   (Followers: 3, SJR: 0.277, CiteScore: 0)
Anales de Pediatría (English Edition)     Full-text available via subscription  
Anales de Pediatría Continuada     Full-text available via subscription  
Analytic Methods in Accident Research     Hybrid Journal   (Followers: 5, SJR: 4.849, CiteScore: 10)
Analytica Chimica Acta     Hybrid Journal   (Followers: 42, SJR: 1.512, CiteScore: 5)
Analytical Biochemistry     Hybrid Journal   (Followers: 185, SJR: 0.633, CiteScore: 2)
Analytical Chemistry Research     Open Access   (Followers: 12, SJR: 0.411, CiteScore: 2)
Analytical Spectroscopy Library     Full-text available via subscription   (Followers: 12)
Anesthésie & Réanimation     Full-text available via subscription   (Followers: 2)
Anesthesiology Clinics     Full-text available via subscription   (Followers: 23, SJR: 0.683, CiteScore: 2)
Angiología     Full-text available via subscription   (SJR: 0.121, CiteScore: 0)
Angiologia e Cirurgia Vascular     Open Access   (Followers: 1, SJR: 0.111, CiteScore: 0)
Animal Behaviour     Hybrid Journal   (Followers: 205, SJR: 1.58, CiteScore: 3)

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Journal Cover
Neurobiology of Disease
Journal Prestige (SJR): 2.674
Citation Impact (citeScore): 5
Number of Followers: 5  
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 0969-9961 - ISSN (Online) 1095-953X
Published by Elsevier Homepage  [3157 journals]
  • The expression of cannabinoid type 1 receptor and 2-arachidonoyl glycerol
           synthesizing/degrading enzymes is altered in basal ganglia during the
           active phase of levodopa-induced dyskinesia
    • Abstract: Publication date: October 2018Source: Neurobiology of Disease, Volume 118Author(s): Estefania Rojo-Bustamante, Miguel Angel Abellanas, Pedro Clavero, Marie-Laure Thiolat, Qin Li, Maria Rosario Luquin, Erwan Bezard, Maria S. Aymerich Management of levodopa-induced dyskinesias (LID) is one of the main challenges in the treatment of Parkinson's disease patients. Mechanisms involved in the appearance of these involuntary movements are not well known but modifications in the activity of different neurotransmitter pathways seem to play an important role. The objective of this study was to determine differences in the expression levels of the endocannabinoid system (ECS) elements that would support a role in LID. The basal ganglia nuclei, putamen, external segment of the globus pallidus (GPe), internal segment of the globus pallidus (GPi), subthalamic nucleus (STN) and substantia nigra (SN) were dissected out from cryostat sections obtained from two groups of parkinsonian monkeys treated with levodopa to induce dyskinesias. One group of dyskinetic animals was sacrificed under the effect of levodopa, during the active phase of LID, and the other group 24 h after the last levodopa dose (OFF levodopa). Biochemical analysis by real-time PCR for ECS elements was performed. CB1 receptor expression was upregulated in the putamen, GPe and STN during the active phase of dyskinesia and downregulated in the same nuclei and in the SN when dyskinetic animals were OFF levodopa. Changes in the 2-arachidonoyl glycerol (2-AG) synthesizing/degrading enzymes affecting the pallidal-subthalamic projections in dyskinetic animals OFF levodopa would suggest that 2-AG may play a role in LID. Anandamide (AEA) synthesizing/degrading enzymes were altered specifically in the GPe of untreated parkinsonian monkeys, suggesting that increased AEA levels may be a compensatory mechanism. These results indicate that the expression of the ECS elements is influenced by alterations in dopaminergic neurotransmission. On one hand, changes in CB1 receptor expression and in the 2-AG synthesizing/degrading enzymes suggest that they could be a therapeutic target for the active phase of LID. On the other hand, AEA metabolism could provide a non-dopaminergic target for symptomatic relief. However, further research is needed to unravel the mechanism of action of the ECS and how they could be modulated for a therapeutic purpose.
  • α-Methyl-α-phenylsuccinimide ameliorates neurodegeneration in a C.
           elegans model of TDP-43 proteinopathy
    • Abstract: Publication date: October 2018Source: Neurobiology of Disease, Volume 118Author(s): Shi Quan Wong, Matthew G. Pontifex, Marie M. Phelan, Chandra Pidathala, Brian C. Kraemer, Jeff W. Barclay, Neil G. Berry, Paul M. O'Neill, Robert D. Burgoyne, Alan Morgan The antiepileptic drug ethosuximide has recently been shown to be neuroprotective in various Caenorhabditis elegans and rodent neurodegeneration models. It is therefore a promising repurposing candidate for the treatment of multiple neurodegenerative diseases. However, high concentrations of the drug are required for its protective effects in animal models, which may impact on its translational potential and impede the identification of its molecular mechanism of action. Therefore, we set out to develop more potent neuroprotective lead compounds based on ethosuximide as a starting scaffold. Chemoinformatic approaches were used to identify compounds with structural similarity to ethosuximide and to prioritise these based on good predicated blood-brain barrier permeability and C. elegans bioaccumulation properties. Selected compounds were initially screened for anti-convulsant activity in a C. elegans pentylenetetrazol-induced seizure assay, as a rapid primary readout of bioactivity; and then assessed for neuroprotective properties in a C. elegans TDP-43 proteinopathy model based on pan-neuronal expression of human A315T mutant TDP-43. The most potent compound screened, α-methyl-α-phenylsuccinimide (MPS), ameliorated the locomotion defects and extended the shortened lifespan of TDP-43 mutant worms. MPS also directly protected against neurodegeneration by reducing the number of neuronal breaks and cell body losses in GFP-labelled GABAergic motor neurons. Importantly, optimal neuroprotection was exhibited by external application of 50 μM MPS, compared to 8 mM for ethosuximide. This greater potency of MPS was not due to bioaccumulation to higher internal levels within the worm, based on 1H-nuclear magnetic resonance analysis. Like ethosuximide, the activity of MPS was abolished by mutation of the evolutionarily conserved FOXO transcription factor, daf-16, suggesting that both compounds act via the same neuroprotective pathway(s).In conclusion, we have revealed a novel neuroprotective activity of MPS that is>100-fold more potent than ethosuximide. This increased potency will facilitate future biochemical studies to identify the direct molecular target(s) of both compounds, as we have shown here that they share a common downstream DAF-16-dependent mechanism of action. Furthermore, MPS is the active metabolite of another approved antiepileptic drug, methsuximide. Therefore, methsuximide may have repurposing potential for treatment of TDP-43 proteinopathies and possibly other human neurodegenerative diseases.
  • Imaging correlates of behavioral impairments: An experimental PET study in
           the rat pilocarpine epilepsy model
    • Abstract: Publication date: October 2018Source: Neurobiology of Disease, Volume 118Author(s): Valentina Di Liberto, R. Maarten van Dijk, Matthias Brendel, Ann-Marie Waldron, Christina Möller, Ines Koska, Isabel Seiffert, Fabio Gualtieri, Franz Josef Gildehaus, Barbara von Ungern-Sternberg, Magdalena Lindner, Sibylle Ziegler, Rupert Palme, Rainer Hellweg, Peter Gass, Peter Bartenstein, Heidrun Potschka Psychiatric comorbidities are prevalent in patients with epilepsy and greatly contribute to the overall burden of disease. The availability of reliable biomarkers to diagnose epilepsy-associated comorbidities would allow for effective treatment and improved disease management. Due to their non-invasive nature, molecular imaging techniques such as positron emission tomography (PET) are ideal tools to measure pathologic changes. In the current study we investigated the potential of [18F]fluoro-2-deoxy-d-glucose ([18F]FDG) and 2′-methoxyphenyl-(N-2′-pyridinyl)-p-18F-fluoro-benzamidoethylpiperazine ([18F]MPPF) as imaging correlates of neurobehavioral comorbidities in the pilocarpine rat model of epilepsy. Findings from rats with epilepsy revealed a regional reduction in [18F]FDG uptake indicating thalamic hypometabolism. In addition, an increase in septal [18F]MPPF binding was observed in rats with spontaneous recurrent seizures. Both thalamic [18F]FDG and septal [18F]MPPF data proved to correlate with behavioral alterations including decreases in luxury behavior such as burrowing and social interaction, and changes in behavioral patterns in anxiety tests. A correlation with seizure frequency was confirmed for thalamic [18F]FDG data. Moreover, thalamic [18F]FDG and septal [18F]MPPF data exhibited a correlation with brain-derived neurotrophic factor (BDNF) serum concentrations, which were lowered in rats with epilepsy.In conclusion, μPET data from rats with pilocarpine-induced epileptogenesis indicate altered septal 5-HT1A receptor binding. Further research is necessary assessing whether septal 5-HT1A receptor binding may serve as an imaging correlate of neuropsychiatric comorbidities in epilepsy patients and for severity assessment in rodent epilepsy models. In contrast, we obtained evidence that [18F]FDG uptake also reflects the severity of epilepsy and, thus, might not constitute a biomarker with sufficient specificity for psychiatric comorbidities. Evidence has been obtained that BDNF might serve as a peripheral circulatory biomarker. Further experimental and clinical assessment is necessary for validation of the marker candidates.
  • Dopamine D2 receptor activation potently inhibits striatal glutamatergic
           transmission in a G2019S LRRK2 genetic model of Parkinson's disease
    • Abstract: Publication date: October 2018Source: Neurobiology of Disease, Volume 118Author(s): Alessandro Tozzi, Valentina Durante, Guendalina Bastioli, Petra Mazzocchetti, Salvatore Novello, Alessandro Mechelli, Michele Morari, Cinzia Costa, Andrea Mancini, Massimiliano Di Filippo, Paolo Calabresi Among genetic abnormalities identified in Parkinson's disease (PD), mutations of the leucine-rich repeat kinase2 (LRRK2) gene, such as the G2019S missense mutation linked to enhanced kinase activity, are the most common. While the complex role of LRRK2 has not been fully elucidated, evidence that mutated kinase activity affects synaptic transmission has been reported. Thus, our aim was to explore possible early alterations of neurotransmission produced by the G2019S LRRK2 mutation in PD. We performed electrophysiological patch-clamp recordings of striatal spiny projection neurons (SPNs) in the G2019S-Lrrk2 knock-in (KI) mouse model of PD, in D1994S kinase-dead (KD), Lrrk2 knock-out (KO) and wild-type (WT) mice. In G2019S Lrrk2 KI mice, basal spontaneous glutamatergic transmission, synaptic facilitation, and NMDA/AMPA ratios were unchanged, whereas the stimulation of dopamine (DA) D2 receptor by quinpirole reduced the spontaneous and evoked excitatory postsynaptic currents (EPSC). Quinpirole reduced the EPSC amplitude of SPNs in KI but not in KD, KO and WT mice, suggesting that the enhanced LRRK2 kinase activity induced by the G2019S mutation is associated with the observed functional alteration of SPNs synaptic transmission. The effect of quinpirole was mediated by a phospholipase C (PLC)-dependent release of endocannabinoid, with subsequent activation of presynaptic cannabinoid receptor 1 and reduced release of glutamate. The key role of DA D2 receptor in reducing glutamatergic output in our LRRK2 genetic model of PD further supports the use of DA agonists in the treatment of early PD patients with LRRK2 mutations to counteract the disease progression.Graphical abstractUnlabelled Image
  • Glycogen synthase kinase-3β inhibition enhances myelination in preterm
           newborns with intraventricular hemorrhage, but not recombinant Wnt3A
    • Abstract: Publication date: October 2018Source: Neurobiology of Disease, Volume 118Author(s): Preeti Dohare, Bokun Cheng, Ehsan Ahmed, Vivek Yadala, Pranav Singla, Sunisha Thomas, Robert Kayton, Zoltan Ungvari, Praveen Ballabh Intraventricular hemorrhage (IVH) in preterm infants results in reduced proliferation and maturation of oligodendrocyte progenitor cells (OPCs), and survivors exhibit reduced myelination and neurological deficits. Wnt signaling regulates OPC maturation and myelination in a context dependent manner. Herein, we hypothesized that the occurrence of IVH would downregulate Wnt signaling, and that activating Wnt signaling by GSK-3β inhibition or Wnt3A recombinant human protein (rh-Wnt3A) treatment might promote maturation of OPCs, myelination of the white matter, and neurological recovery in premature rabbits with IVH. These hypotheses were tested in autopsy samples from preterm infants and in a rabbit model of IVH. Induction of IVH reduced expressions of activated β-catenin, TCF-4, and Axin2 transcription factors in preterm newborns. Both AR-A014418 (ARA) and Wnt-3A treatment activated Wnt signaling. GSK-3β inhibition by intramuscular ARA treatment accelerated maturation of OPCs, myelination, and neurological recovery in preterm rabbits with IVH compared to vehicle controls. In contrast, intracerebroventricular rh-Wnt3A treatment failed to enhance myelination and neurological function in rabbits with IVH. ARA treatment reduced microglia infiltration and IL1β expression in rabbits with IVH relative to controls, whereas Wnt3A treatment elevated TNFα, IL1β, and IL6 expression without affecting microglia density. GSK-3β inhibition downregulated, while rh-Wnt3A treatment upregulated Notch signaling; and none of the two treatments affected the Sonic-Hedgehog pathway. The administration of ARA or rh-Wnt3A did not affect gliosis. The data suggest that GSK-3β inhibition promoted myelination by suppressing inflammation and Notch signaling; and Wnt3A treatment failed to enhance myelination because of its pro-inflammatory activity and synergy with Notch signaling. GSK-3β inhibitors might improve the neurological outcome of preterm infants with IVH.
  • Bexarotene protects against neurotoxicity partially through a
           PPARγ-dependent mechanism in mice following traumatic brain injury
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Junchi He, Han Liu, Jianjun Zhong, Zongduo Guo, Jingchuan Wu, Hongrong Zhang, Zhijian Huang, Li Jiang, Hui Li, Zhaosi Zhang, Liu Liu, Yue Wu, Lingjun Qi, Xiaochuan Sun, Chongjie Cheng Traumatic brain injury (TBI) causes a high rate of mortality and disability worldwide, and there exists almost none effective drugs to protect against TBI. Neurotoxicity occurring after TBI can be derived from microglia and astrocytes, and causes neuronal death and synapse loss. Bexarotene has been demonstrated to protect neurons in CNS diseases. In the present study, we aimed to investigate the potential role of bexarotene in protecting against neurotoxicity after TBI, as well as the underlying mechanism. The controlled cortical impact (CCI) model was established on adult C57BL/6 mice, followed by intraperitoneal administration of bexarotene for 14 consecutive days. We found that bexarotene improved sensorimotor function and cognitive recovery in CCI mice. In addition, bexarotene decreased neuronal death and synapse loss, as well as inhibited apoptotic cascade. Moreover, bexarotene treatment reduced M1 microglia polarization, microglia-derived pro-inflammatory cytokines, and the number of A1 astrocytes after CCI. These effects of bexarotene were partially abolished by T0070907, an antagonist of peroxisome proliferator–activated receptor gamma (PPARγ). Additionally, bexarotene enhanced nuclear translocation and transcriptional activity of PPARγ. These findings show that bexarotene inhibits neurotoxicity in mice after TBI, at least in part through a PPARγ-dependent mechanism.
  • Beta burst coupling across the motor circuit in Parkinson's disease
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Gerd Tinkhauser, Flavie Torrecillos, Yann Duclos, Huiling Tan, Alek Pogosyan, Petra Fischer, Romain Carron, Marie-Laure Welter, Carine Karachi, Wim Vandenberghe, Bart Nuttin, Tatiana Witjas, Jean Régis, Jean-Philippe Azulay, Alexandre Eusebio, Peter Brown Exaggerated activity in the beta band (13–35 Hz) is a hallmark of basal ganglia signals in patients with Parkinson's disease (PD). Beta activity however is not constantly elevated, but comes in bursts. In previous work we showed that the longer beta bursts are maintained, the more the oscillatory synchronisation within the subthalamic nucleus (STN) increases, which is posited to limit the information coding capacity of local circuits. Accordingly, a higher incidence of longer bursts correlates positively with clinical impairment, while the opposite is true for short, more physiological bursts. Here, we test the hypothesis that beta bursts not only indicate local synchronisation within the STN, but also phasic coupling across the motor network and hence entail an even greater restriction of information coding capacity in patients with PD. Local field potentials from the subthalamic nucleus and EEG over the motor cortex area were recorded in nine PD patients after temporary lead externalization after surgery for deep brain stimulation and overnight withdrawal of levodopa. Beta bursts were defined as periods exceeding the 75th percentile of signal amplitude and the coupling between bursts was considered using two distinct measurements, first the % overlapping (%OVL) as a feature of the amplitude coupling and secondly the phase synchrony index (PSI) to measure the phase coupling between regions. %OVL between STN and cortex and between the left and the right STN was higher than expected between the regions than if they had been independent. Similarly, PSI was higher during bursts as opposed to non-bursts periods. In addition, %OVL was greater for long compared to short bursts. Our results support the hypothesis that beta bursts involve long-range coupling between structures in the basal ganglia-cortical network. The impact of this is greater during long as opposed to short duration beta bursts. Accordingly, we posit that episodes of simultaneously elevated coupling across multiple structures in the basal ganglia-cortical circuit further limit information coding capacity and may have further impact upon motor impairment.
  • Protein coding mitochondrial-targeted RNAs rescue mitochondrial disease
           in vivo
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Desiree M. Markantone, Atif Towheed, Aaron T. Crain, Jessica M. Collins, Alicia M. Celotto, Michael J. Palladino Mitochondrial encephalomyopathies (MEs) result from mutations in mitochondrial genes critical to oxidative phosphorylation. Severe and untreatable ME results from mutations affecting each endogenous mitochondrial encoded gene, including all 13 established protein coding genes. Effective techniques to manipulate mitochondrial genome are limited and targeted mitochondrial protein expression is currently unavailable. Here we report the development of a mitochondrial-targeted RNA expression (mtTRES) vector capable of protein expression within mitochondria (mtTRESPro). We demonstrate that mtTRESPro expressed RNAs are targeted to mitochondria and are capable of being translated using EGFP encoded constructs in vivo. We additionally test mtTRESPro constructs encoding wild type ATP6 for their ability to rescue an established ATP61Drosophila model of ME. Genetic rescue is examined including tests with co-expression of mitochondrial targeted translational inhibitors TLI-NCL::ATP6 RNAs that function to reduce expression of the endogenous mutant protein. The data demonstrate allotopic RNA expression of mitochondrial targeted wild type ATP6 coding RNAs are sufficient to partially rescue a severe and established animal model of ME but only when combined with a method to inhibit mutant protein expression, which likely competes for incorporation into complex V.
  • Glutamatergic nervous system degeneration in a C. elegans TauA152T
           tauopathy model involves pathways of excitotoxicity and Ca2+ dysregulation
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Bikash Choudhary, Eckhard Mandelkow, Eva-Maria Mandelkow, Ghulam Jeelani Pir Mutations in the gene encoding Tau (MAPT-microtubule-associated protein tau) cause a group of neurodegenerative diseases called tauopathies. A recently identified Tau variant, p.A152T, has been reported as a risk factor for frontotemporal dementia-related disorders and Alzheimer disease. However, the mechanism for the pathologies still remain poorly understood. Transgenic Caenorhabditis elegans expressing mutant 2N4R-TauA152T (TauAT) panneuronally show locomotor defects, neurodegeneration and accelerated aging. Here we report that, in TauAT animals, the glutamatergic nervous system is at a high risk of progressive neuronal loss. We present genetic data that this loss occurs predominantly through necrosis. The neuronal loss is caused by several determinants, such as altered adenylyl cyclase (type AC9) pathway, prevalence of excitotoxicity-like conditions, aging-related factors and finally dyshomeostasis of intracellular calcium (Ca2+). The study provides novel insights into the mechanisms involved in selective loss of glutamatergic neurons in a TauAT tauopathy model which could point to new therapeutic targets.Graphical abstractUnlabelled Image
  • Neuronal levels and sequence of tau modulate the power of brain rhythms
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Melanie Das, Sumihiro Maeda, Bozhong Hu, Gui-Qiu Yu, Weikun Guo, Isabel Lopez, Xinxing Yu, Chao Tai, Xin Wang, Lennart Mucke Neural network dysfunction may contribute to functional decline and disease progression in neurodegenerative disorders. Diverse lines of evidence suggest that neuronal accumulation of tau promotes network dysfunction and cognitive decline. The A152T-variant of human tau (hTau-A152T) increases the risk of Alzheimer's disease (AD) and several other tauopathies. When overexpressed in neurons of transgenic mice, it causes age-dependent neuronal loss and cognitive decline, as well as non-convulsive epileptic activity, which is also seen in patients with AD. Using intracranial EEG recordings with electrodes implanted over the parietal cortex, we demonstrate that hTau-A152T increases the power of brain oscillations in the 0.5–6 Hz range more than wildtype human tau in transgenic lines with comparable levels of human tau protein in brain, and that genetic ablation of endogenous tau in Mapt−/− mice decreases the power of these oscillations as compared to wildtype controls. Suppression of hTau-A152T production in doxycycline-regulatable transgenic mice reversed their abnormal network activity. Treatment of hTau-A152T mice with the antiepileptic drug levetiracetam also rapidly and persistently reversed their brain dysrhythmia and network hypersynchrony. These findings suggest that both the level and the sequence of tau modulate the power of specific brain oscillations. The potential of EEG spectral changes as a biomarker deserves to be explored in clinical trials of tau-lowering therapeutics. Our results also suggest that levetiracetam treatment is able to counteract tau-dependent neural network dysfunction. Tau reduction and levetiracetam treatment may be of benefit in AD and other conditions associated with brain dysrhythmias and network hypersynchrony.
  • Chronic nicotine improves cognitive and social impairment in mice
           overexpressing wild type α-synuclein
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Sudhakar R. Subramaniam, Iddo Magen, Nicholas Bove, Chunni Zhu, Vincent Lemesre, Garima Dutta, Chris Jean Elias, Henry A. Lester, Marie-Francoise Chesselet In addition to dopaminergic and motor deficits, patients with Parkinson's disease (PD) suffer from non-motor symptoms, including early cognitive and social impairment, that do not respond well to dopaminergic therapy. Cholinergic deficits may contribute to these problems, but cholinesterase inhibitors have limited efficacy. Mice over-expressing α-synuclein, a protein critically associated with PD, show deficits in cognitive and social interaction tests, as well as a decrease in cortical acetylcholine. We have evaluated the effects of chronic administration of nicotine in mice over-expressing wild type human α-synuclein under the Thy1-promoter (Thy1-aSyn mice). Nicotine was administered subcutaneously by osmotic minipump for 6 months from 2 to 8 months of age at 0.4 mg/kg/h and 2.0 mg/kg/h. The higher dose was toxic in the Thy1-aSyn mice, but the low dose was well tolerated and both doses ameliorated cognitive impairment in Y-maze performance after 5 months of treatment. In a separate cohort of Thy1-aSyn mice, nicotine was administered at the lower dose for one month beginning at 5 months of age. This treatment partially eliminated the cognitive deficit in novel object recognition and social impairment. In contrast, chronic nicotine did not improve motor deficits after 2, 4 or 6 months of treatment, nor modified α-synuclein aggregation, tyrosine hydroxylase immunostaining, synaptic and dendritic markers, or microglial activation in Thy1-aSyn mice. These results suggest that cognitive and social impairment in synucleinopathies like PD may result from deficits in cholinergic neurotransmission and may benefit from chronic administration of nicotinic agonists.
  • Newfound effect of N-acetylaspartate in preventing and reversing
           aggregation of amyloid-beta in vitro
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Jean-Pierre Dollé, Jeffrey M. Rodgers, Kevin D. Browne, Thomas Troxler, Feng Gai, Douglas H. Smith Although N-acetylaspartate (NAA) has long been recognized as the most abundant amino acid in neurons by far, its primary role has remained a mystery. Based on its unique tertiary structure, we explored the potential of NAA to modulate aggregation of amyloid-beta (Aβ) peptide 1-42 via multiple corroborating aggregation assays along with electron microscopy. Thioflavin-T fluorescence assay demonstrated that at physiological concentrations, NAA substantially inhibited the initiation of Aβ fibril formation. In addition, NAA added after 25 min of Aβ aggregation was shown to break up preformed fibrils. Electron microscopy analysis confirmed the absence of mature fibrils following NAA treatment. Furthermore, fluorescence correlation spectroscopy and dynamic light scattering measurements confirmed significant reductions in Aβ fibril hydrodynamic radius following treatment with NAA. These results suggest that physiological levels of NAA could play an important role in controlling Aβ aggregation in vivo where they are both found in the same neuronal compartments.
  • V363I and V363A mutated tau affect aggregation and neuronal dysfunction
           differently in C. elegans
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Federica Morelli, Margherita Romeo, Maria Monica Barzago, Marco Bolis, Davide Mattioni, Giacomina Rossi, Fabrizio Tagliavini, Antonio Bastone, Mario Salmona, Luisa Diomede Mutations in the microtubule-associated protein tau (MAPT) gene have been linked to a heterogeneous group of progressive neurodegenerative disorders commonly called tauopathies. From patients with frontotemporal lobar degeneration with distinct atypical clinical phenotypes, we recently identified two new mutations on the same codon, in position 363 of the MAPT gene, which resulted in the production of Val-to-Ala (tauV363A) or Val-to-Ile (tauV363I) mutated tau. These substitutions specifically affected microtubule polymerization and propensity of tau to aggregate in vitro suggesting that single amino acid modification may dictate the fate of the neuropathology. To clarify whether tauV363A and tauV363I affect protein misfolding differently in vivo driving certain phenotypes, we generated new transgenic C. elegans strains. Human 2N4R tau carrying the mutation was expressed in all the neurons of worms. The behavioral defects, misfolding and proteotoxicity caused by the tauV363A and tauV363I mutated proteins were compared to that induced by the expression of wild-type tau (tauwt). Pan-neuronal expression of human 2N4R tauWT in worms resulted in a neuromuscular defect with characteristics of a neurodegenerative phenotype. This defect was worsened by the expression of mutated proteins which drive distinct neuronal dysfunctions and synaptic impairments involving, in transgenic worms expressing tauV363A (V363A) also a pharyngeal defect never linked before to other mutations. The two mutations differently affected the tau phosphorylation and misfolding propensities: tauV363I was highly phosphorylated on epitopes corresponding to Thr231 and Ser202/Thr205, and accumulated as insoluble tau assemblies whereas tauV363A showed a greater propensity to form soluble oligomeric assemblies. These findings uphold the role of a single amino acid substitution in specifically affecting the ability of tau to form soluble and insoluble assemblies, opening up new perspectives in the pathogenic mechanism underlying tauopathies.
  • Correlation between cortical beta power and gait speed is suppressed in a
           parkinsonian model, but restored by therapeutic deep brain stimulation
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Christian A. Polar, Rahul Gupta, Mark J. Lehmkuhle, Alan D. Dorval The motor cortex and subthalamic nucleus (STN) of patients with Parkinson's disease (PD) exhibit abnormally high levels of electrophysiological oscillations in the ~12–35 Hz beta-frequency range. Recent studies have shown that beta is partly carried forward to regulate future motor states in the healthy condition, suggesting that steady state beta power is lower when a sequence of movements occurs in a short period of time, such as during fast gait. However, whether this relationship between beta power and motor states persists upon parkinsonian onset or in response to effective therapy is unclear. Using a 6-hydroxy dopamine (6-OHDA) rat model of PD and a custom-built behavioral and neurophysiological recording system, we aimed to elucidate a better understanding of the mechanisms underlying cortical beta power and PD symptoms. In addition to elevated levels of beta oscillations, we show that parkinsonian onset was accompanied by a decoupling of movement intensity — quantified as gait speed — from cortical beta power. Although subthalamic deep brain stimulation (DBS) reduced general levels of beta oscillations in the cortex of all PD animals, the brain's capacity to regulate steady state levels of beta power as a function of movement intensity was only restored in animals with therapeutic DBS. We propose that, in addition to lowering general levels of cortical beta power, restoring the brain's ability to maintain this inverse relationship is critical for effective symptom suppression.
  • Pretangle pathology within cholinergic nucleus basalis neurons coincides
           with neurotrophic and neurotransmitter receptor gene dysregulation during
           the progression of Alzheimer's disease
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Chelsea T. Tiernan, Stephen D. Ginsberg, Bin He, Sarah M. Ward, Angela L. Guillozet-Bongaarts, Nicholas M. Kanaan, Elliott J. Mufson, Scott E. Counts Cholinergic basal forebrain neurons of the nucleus basalis of Meynert (nbM) regulate attentional and memory function and are exquisitely prone to tau pathology and neurofibrillary tangle (NFT) formation during the progression of Alzheimer's disease (AD). nbM neurons require the neurotrophin nerve growth factor (NGF), its cognate receptor TrkA, and the pan-neurotrophin receptor p75NTR for their maintenance and survival. Additionally, nbM neuronal activity and cholinergic tone are regulated by the expression of nicotinic (nAChR) and muscarinic (mAChR) acetylcholine receptors as well as receptors modulating glutamatergic and catecholaminergic afferent signaling. To date, the molecular and cellular relationships between the evolution of tau pathology and nbM neuronal survival remain unknown. To address this knowledge gap, we profiled cholinotrophic pathway genes within nbM neurons immunostained for pS422, a pretangle phosphorylation event preceding tau C-terminal truncation at D421, or dual-labeled for pS422 and TauC3, a later stage tau neo-epitope revealed by this same C-terminal truncation event, via single-population custom microarray analysis. nbM neurons were obtained from postmortem tissues from subjects who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), or mild/moderate AD. Quantitative analysis revealed significant downregulation of mRNAs encoding TrkA as well as TrkB, TrkC, and the Trk-mediated downstream pro-survival kinase Akt in pS422+ compared to unlabeled, pS422-negative nbM neurons. In addition, pS422+ neurons displayed a downregulation of transcripts encoding NMDA receptor subunit 2B, metabotropic glutamate receptor 2, D2 dopamine receptor, and β1 adrenoceptor. By contrast, transcripts encoding p75NTR were downregulated in dual-labeled pS422+/TauC3+ neurons. Appearance of the TauC3 epitope was also associated with an upregulation of the α7 nAChR subunit and differential downregulation of the β2 nAChR subunit. Notably, we found that gene expression patterns for each cell phenotype did not differ with clinical diagnosis. However, linear regression revealed that global cognition and Braak stage were predictors of select transcript changes within both unlabeled and pS422+/TauC3− neurons. Taken together, these cell phenotype-specific gene expression profiling data suggest that dysregulation of neurotrophic and neurotransmitter signaling is an early pathogenic mechanism associated with NFT formation in vulnerable nbM neurons and cognitive decline in AD, which may be amenable to therapeutic intervention early in the disease process.
  • Does inflammation precede tau aggregation in early Alzheimer's
           disease' A PET study
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Peter Parbo, Rola Ismail, Michael Sommerauer, Morten G. Stokholm, Allan K. Hansen, Kim V. Hansen, Ali Amidi, Jeppe L. Schaldemose, Hanne Gottrup, Hans Brændgaard, Simon F. Eskildsen, Per Borghammer, Rainer Hinz, Joel Aanerud, David J. Brooks Objective: Our aim was to assess with positron emission tomography (PET) the temporal and spatial inter-relationships between levels of cortical microglial activation and the aggregated amyloid-β and tau load in mild cognitive impairment (MCI) and early Alzheimer's disease (AD).Methods: Six clinically probable AD and 20 MCI subjects had inflammation (11C-(R)-PK11195), amyloid (11C-PiB) and tau (18F-flortaucipir) PET, magnetic resonance imaging (MRI) and a neuropsychological assessment. Parametric images of tracer binding were interrogated at a voxel level and by region of interest analyses.Results: 55% of MCI and 83% of AD subjects had a high amyloid-β load. We have previously reported that clusters of correlated amyloid and inflammation levels are present in cortex. Here we found no correlation between levels of inflammation (11C-(R)-PK11195 BPND) and tau (18F-flortaucipir SUVR) or MMSE scores in high amyloid-β cases.Interpretation: While correlated levels of amyloid-β and inflammation can be seen in MCI, we did not detect an association between levels of cortical tau tangles and inflammation in our series of high amyloid-β cases. High levels of inflammation could be seen in amyloid-β positive MCI cases where 18F-flortaucipir signals were low suggesting microglial activation precedes tau tangle formation. Inflammation levels were higher in high amyloid-β MCI than in early AD cases, compatible with it initially playing a protective role.
  • Organophosphate pesticide chlorpyrifos impairs STAT1 signaling to induce
           dopaminergic neurotoxicity: Implications for mitochondria mediated
           oxidative stress signaling events
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Neeraj Singh, Vivek Lawana, Jie Luo, Phang Phong, Ahmed Abdalla, Bharathi Palanisamy, Dharmin Rokad, Souvarish Sarkar, Huajun Jin, Vellareddy Anantharam, Anumantha G. Kanthasamy, Arthi Kanthasamy The organophosphate (OP) pesticide chlorpyrifos (CPF), used in agricultural settings, induces developmental and neurological impairments. Recent studies using in vitro cell culture models have reported CPF exposure to have a positive association with mitochondria-mediated oxidative stress response and dopaminergic cell death; however, the mechanism by which mitochondrial reactive oxygen species (ROS) contribute to dopaminergic cell death remains unclear. Therefore, we hypothesized that STAT1, a transcription factor, causes apoptotic dopaminergic cell death via mitochondria-mediated oxidative stress mechanisms. Here we show that exposure of dopaminergic neuronal cells such as N27 cells (immortalized murine mesencephalic dopaminergic cells) to CPF resulted in a dose-dependent increase in apoptotic cell death as measured by MTS assay and DNA fragmentation. Similar effects were observed in CPF-treated human dopaminergic neuronal cells (LUHMES cells), with an associated increase in mitochondrial dysfunction. Moreover, CPF (10 μM) induced time-dependent increase in STAT1 activation coincided with the collapse of mitochondrial transmembrane potential, increase in ROS generation, proteolytic cleavage of protein kinase C delta (PKCδ), inhibition of the mitochondrial basal oxygen consumption rate (OCR), with a concomitant reduction in ATP-linked OCR and reserve capacity, increase in Bax/Bcl-2 ratio and enhancement of autophagy. Additionally, by chromatin immunoprecipitation (ChIP), we demonstrated that STAT1 bound to a putative regulatory sequence in the NOX1 and Bax promoter regions in response to CPF in N27 cells. Interestingly, overexpression of non-phosphorylatable STAT1 mutants (STAT1Y701F and STAT1S727A) but not STAT1 WT construct attenuated the cleavage of PKCδ and ultimately cell death in CPF-treated cells. Furthermore, small interfering RNA knockdown demonstrated STAT1 to be a critical regulator of autophagy and mitochondria-mediated proapoptotic cell signaling events after CPF treatment in N27 cells. Finally, oral administration of CPF (5 mg/kg) in postnatal rats (PNDs 27–61) induced motor deficits, and nigrostriatal dopaminergic neurodegeneration with a concomitant induction of STAT1-dependent proapoptotic cell signaling events. Conversely, co-treatment with mitoapocynin (a mitochondrially-targeted antioxidant) and CPF rescued motor deficits, and restored dopaminergic neuronal survival via abrogation of STAT1-dependent proapoptotic cell signaling events. Taken together, our study identifies a novel mechanism by which STAT1 regulates mitochondria-mediated oxidative stress response, PKCδ activation and autophagy. In this context, the phosphorylation of Tyrosine 701 and Serine 727 in STAT1 was found to be essential for PKCδ cleavage. By attenuating mitochondrial-derived ROS, mitoapocynin may have therapeutic applications for reversing CPF-induced dopaminergic neurotoxicity and associated neurobehavioral deficits as well as neurodegenerative diseases.
  • Blockade of adenosine A2A receptors recovers early deficits of memory and
           plasticity in the triple transgenic mouse model of Alzheimer's disease
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): António C. Silva, Cristina Lemos, Francisco Q. Gonçalves, Anna V. Pliássova, Nuno J. Machado, Henrique B. Silva, Paula M. Canas, Rodrigo A. Cunha, João Pedro Lopes, Paula Agostinho Alzheimer's disease (AD) begins with a deficit of synaptic function and adenosine A2A receptors (A2AR) are mostly located in synapses controlling synaptic plasticity. The over-activation of adenosine A2A receptors (A2AR) causes memory deficits and the blockade of A2AR prevents memory damage in AD models. We now enquired if this prophylactic role of A2AR might be extended to a therapeutic potential. We used the triple transgenic model of AD (3xTg-AD) and defined that the onset of memory dysfunction occurred at 4 months of age in the absence of locomotor or emotional alterations. At the onset of memory deficits, 3xTg mice displayed a decreased density of markers of excitatory synapses (10.6 ± 3.8% decrease of vGluT1) without neuronal or glial overt damage and an increase of synaptic A2AR in the hippocampus (130 ± 22%). After the onset of memory deficits in 3xTg-AD mice, a three weeks treatment with the selective A2AR antagonist normalized the up-regulation of hippocampal A2AR and restored hippocampal-dependent reference memory, as well as the decrease of hippocampal synaptic plasticity (60.0 ± 3.7% decrease of long-term potentiation amplitude) and the decrease of global (syntaxin-I) and glutamatergic synaptic markers (vGluT1). These findings show a therapeutic-like ability of A2AR antagonists to recover synaptic and memory dysfunction in early AD.
  • Latent classes of mild cognitive impairment are associated with clinical
           outcomes and neuropathology: Analysis of data from the National
           Alzheimer's Coordinating Center
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): John J. Hanfelt, Limin Peng, Felicia C. Goldstein, James J. Lah Given the importance of identifying prodromes of dementia with specific etiologies, we assessed whether seven latent classes of mild cognitive impairment (MCI), defined empirically based on cognitive, functional, and neuropsychiatric information at initial visit, are associated with distinct clinical outcomes and neuropathological features. We separated 6034 participants with a baseline diagnosis of MCI into seven latent classes using previously defined criteria. We found that these latent classes of MCI differed significantly in their clinical outcomes, survival time, and neuropathology. Two amnestic multi-domain subgroups, as well as two other subgroups with functional impairments and neuropsychiatric disturbances, were at higher risk of not only a ‘pure’ form of Alzheimer's disease (AD) pathology, but also a ‘mixed’ pathology consisting of both AD and vascular features. Moreover, the seven latent classes had different risks of Lewy bodies, hippocampal sclerosis, and frontotemporal lobar degeneration (FTLD). This study indicates that data-driven subgroups of MCI are clinicopathologically informative and, with refinement, could lead to targeted interventions focused on each etiology.
  • Multiple sclerosis and mixed microbial infections. Direct identification
           of fungi and bacteria in nervous tissue
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Ruth Alonso, Ana M. Fernández-Fernández, Diana Pisa, Luis Carrasco Multiple sclerosis (MS) is the prototypical inflammatory disease of the central nervous system (CNS), leading to multifocal demyelination and neurodegeneration. The etiology of this incurable disease is unknown and remains a matter of intensive research. The possibility that microbial infections, such as viruses or bacteria, can trigger an autoimmune reaction in CNS tissue has been suggested. However, the recent demonstration that bacteria are present in CNS tissue points to a direct involvement of microbial infections in the etiology of MS. In the present study, we provide the first evidence of fungal infection in CNS tissue of MS patients, and demonstrate that fungal DNA from different species can be detected in the CNS. We used, nested PCR assays together with next-generation sequencing to identify the fungal species in the nervous tissue of 10 patients with MS. Strikingly, Trichosporon mucoides was found in the majority of MS patients, and particularly high levels of this fungus were found in two patients. Importantly, T. mucoides was not detected in the CNS of control subjects. We were also able to visualize fungal structures in CNS tissue sections by immunohistochemistry using specific antifungal antibodies, which also revealed the accumulation of a number of microbial cells in microfoci. Again, microbial structures were not observed in CNS sections from controls. In addition to fungi, neural tissue from MS patients was also positive for bacteria. In conclusion, our present observations point to the novel concept that MS could be caused by polymicrobial infections. Thus, mycosis of the CNS may be accompanied by opportunistic bacterial infection, promoting neuroinflammation and directly causing focal lesions, followed by demyelination and axonal injury.
  • Cocaine-mediated activation of microglia and microglial MeCP2 and BDNF
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Bianca Cotto, Hongbo Li, Ronald F. Tuma, Sara Jane Ward, Dianne Langford The molecular substrates underlying cocaine reinforcement and addiction have been studied for decades, with a primary focus on signaling molecules involved in modulation of neuronal communication. Brain-derived neurotrophic factor (BDNF) is an important signaling molecule involved in neuronal dendrite and spine modulation. Methyl CpG binding protein 2 (MeCP2) binds to the promoter region of BDNF to negatively regulate its expression and cocaine can recruit MeCP2 to alter the expression of genes such as BDNF that are involved in synaptic plasticity. For several decades, BDNF has been implicated in mediating synaptic plasticity associated with cocaine abuse, and most studies report that neurons are the primary source for BDNF production in the brain. The current study assessed the effects of intravenous cocaine self-administration on microglial activation, and MeCP2 and BDNF expression in reward regions of the brain in vivo, as well as determined specific effects of cocaine exposure on MeCP2 and BDNF expression in human primary neurons and microglia. The results from this study highlight a distinct molecular pathway in microglia through which cocaine increases BDNF, including the phosphorylation of MeCP2 its subsequent translocation from the nucleus to the cytosol, which frees the BDNF promoter and permits its transcriptional activation. Results from these studies show for the first time that cocaine self-administration increases microglial activation, and that microglial MeCP2 is a sensitive target of cocaine resulting in increased release of BDNF from microglia, and possibly contributing to cocaine-induced synaptic plasticity.
  • Selective NLRP3 inflammasome inhibitor reduces neuroinflammation and
           improves long-term neurological outcomes in a murine model of traumatic
           brain injury
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Xin Xu, Dongpei Yin, Honglei Ren, Weiwei Gao, Fei Li, Dongdong Sun, Yingang Wu, Shuai Zhou, Li Lyu, Mengchen Yang, Jianhua Xiong, Lulu Han, Rongcai Jiang, Jianning Zhang The nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory response has emerged as a prominent contributor to the pathophysiological processes of traumatic brain injury (TBI). Recently, a potent, selective, small-molecule NLRP3 inflammasome inhibitor, MCC950, was described. Here, we investigated the effect of MCC950 on inflammatory brain injury and long-term neurological outcomes in a mouse model of TBI. Male C57/BL6 mice were subjected to TBI using the controlled cortical impact injury (CCI) system. Western blotting, flow cytometry, and immunofluorescence assays were utilized to analyze post-traumatic NLRP3 inflammasome expression and determine its cellular source. We found that NLRP3 inflammasome expression was significantly increased in the peri-contusional cortex and that microglia were the primary source of this expression. The effects of MCC950 on mice with TBI were then determined using post-assessments including analyses of neurological deficits, brain water content, traumatic lesion volume, neuroinflammation, blood-brain barrier (BBB) integrity, and cell death. MCC950 treatment resulted in a better neurological outcome after TBI by alleviating brain edema, reducing lesion volume, and improving long-term motor and cognitive functions. The therapeutic window for MCC950 against TBI was as long as 6 h. Furthermore, the neuroprotective effect of MCC950 was associated with reduced microglial activation, leukocyte recruitment, and pro-inflammatory cytokine production. In addition, MCC950 preserved BBB integrity, alleviated TBI-induced loss of tight junction proteins, and attenuated cell death. Notably, the efficacy of MCC950 was abolished in microglia-depleted mice. These results indicate that microglia-derived NLRP3 inflammasome may be primarily involved in the inflammatory response to TBI, and specific NLRP3 inflammasome inhibition using MCC950 may be a promising therapeutic approach for patients with TBI.
  • Hereditary sensory neuropathy type 1-associated deoxysphingolipids cause
           neurotoxicity, acute calcium handling abnormalities and mitochondrial
           dysfunction in vitro
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Emma R. Wilson, Umaiyal Kugathasan, Andrey Y. Abramov, Alex J. Clark, David L.H. Bennett, Mary M. Reilly, Linda Greensmith, Bernadett Kalmar Hereditary sensory neuropathy type 1 (HSN-1) is a peripheral neuropathy most frequently caused by mutations in the SPTLC1 or SPTLC2 genes, which code for two subunits of the enzyme serine palmitoyltransferase (SPT). SPT catalyzes the first step of de novo sphingolipid synthesis. Mutations in SPT result in a change in enzyme substrate specificity, which causes the production of atypical deoxysphinganine and deoxymethylsphinganine, rather than the normal enzyme product, sphinganine. Levels of these abnormal compounds are elevated in blood of HSN-1 patients and this is thought to cause the peripheral motor and sensory nerve damage that is characteristic of the disease, by a largely unresolved mechanism. In this study, we show that exogenous application of these deoxysphingoid bases causes dose- and time-dependent neurotoxicity in primary mammalian neurons, as determined by analysis of cell survival and neurite length. Acutely, deoxysphingoid base neurotoxicity manifests in abnormal Ca2+ handling by the endoplasmic reticulum (ER) and mitochondria as well as dysregulation of cell membrane store-operated Ca2+ channels. The changes in intracellular Ca2+ handling are accompanied by an early loss of mitochondrial membrane potential in deoxysphingoid base-treated motor and sensory neurons. Thus, these results suggest that exogenous deoxysphingoid base application causes neuronal mitochondrial dysfunction and Ca2+ handling deficits, which may play a critical role in the pathogenesis of HSN-1.Graphical abstractGraphical illustration demonstrating the proposed pathomechanism of the toxic, atypical deoxysphinganine and deoxymethylsphinganine, produced by mutant SPT in HSN-1.The toxic sphingoid bases DSp and DMSp (or downstream metabolites) are released into the extracellular space where they destabilize neuronal cell membranes, resulting in dysfunction of neuronal ion channels such as store-operated Ca2+ (SOC) channels, upon stimulation. This results in elevated Ca2+ entry when SOC channels open, which is buffered by mitochondria. This increase in mitochondrial Ca2+ uptake in turn results in mitochondrial dysfunction, leading to loss of mitochondrial membrane potential and ultimately dysfunction of cellular processes and neuronal degeneration. (DSp: deoxysphinganine; DMSp: deoxymethylsphinganine).Unlabelled Image
  • Pharmaco-genetic therapeutics targeting parvalbumin neurons attenuate
           temporal lobe epilepsy
    • Abstract: Publication date: September 2018Source: Neurobiology of Disease, Volume 117Author(s): Ying Wang, Jiao Liang, Liying Chen, Yating Shen, Junli Zhao, Cenglin Xu, Xiaohua Wu, Heming Cheng, Xiaoying Ying, Yi Guo, Shuang Wang, Yudong Zhou, Yi Wang, Zhong Chen Temporal lobe epilepsy (TLE) is the most common type of epilepsy and is often medically refractory. Previous studies suggest that selective pharmaco-genetic inhibition of pyramidal neurons has therapeutic value for the treatment of epilepsy, however there is a risk of disrupting normal physical functions. Here, we test whether pharmaco-genetic activation of parvalbumin neurons, which are transgenetically transduced with the modified muscarinic receptor hM3Dq can attenuate TLE. We found that pharmaco-genetic activation of hippocampal parvalbumin neurons in epileptogenic zone not only significantly extends the latency to different seizure stages and attenuates seizure activities in acute seizure model, but also greatly alleviates the severity of seizure onsets in two chronic epilepsy models. This manipulation did not affect the normal physical function evaluated in various cognitive tasks. Further, the activation of parvalbumin neurons produced an inhibition on parts of surrounding pyramidal neurons, and the direct inactivation of pyramidal neurons via the viral expression of a modified muscarinic receptor hM4Di produced a similar anti-ictogenic effect. Interestingly, pharmaco-genetic inactivation of pyramidal neurons was more sensitive to impair cognitive function. Those data demonstrated that pharmaco-genetic seizure attenuation through targeting parvalbumin neurons rather than pyramidal neurons may be a novel and relatively safe approach for treating refractory TLE.
  • Pharmacogenetic neuronal stimulation increases human tau pathology and
           trans-synaptic spread of tau to distal brain regions in mice
    • Abstract: Publication date: Available online 7 July 2018Source: Neurobiology of DiseaseAuthor(s): M.K. Schultz, R. Gentzel, M. Usenovic, C. Gretzula, C. Ware, S. Parmentier-Batteur, J.B. Schachter, H.A. Zariwala In Alzheimer's Disease (AD), tau pathology has a spatiotemporally distinct pattern of progressive spread along anatomically connected neural pathways. Extracellular tau in the brain interstitial space increases in response to neuronal activity suggesting that neural activity may also drive pathogenic tau spread. Here we tested the hypothesis that neuronal activity drives human Tau (hTau) release and trans-synaptic spread to neuroanatomically connected regions. We used AAV to overexpress wild type full-length hTau and an excitatory DREADD (Designer Receptors Exclusively Activated by a Designer Drug) in mouse primary hippocampal cultures and determined that excitatory stimulation with the DREADD ligand clozapine N-oxide (CNO) promoted extracellular hTau release. We translated this approach to an in vivo model and used AAV to express hTau and the excitatory DREADD in the ventral hippocampus of wild type mice, P301L hTau-expressing mice, or tau knockout mice. Six to eight weeks following AAV injection, we determined that CNO treatment in DREADD-expressing mice resulted in increased hTau pathology and hTau spread to distal brain regions compared to unstimulated controls (CNO in non-DREADD mice, or vehicle in DREADD mice). The results highlight a potentially disease relevant exacerbation of tau pathology in response to elevated neuronal activity. This model underscores the propensity of non-mutant hTau to undergo neuronal spreading, as seen in AD. The model can translate to other preclinical species and can be used to evaluate modes of tau transmission and test the efficacy of therapeutic approaches that target tau or hyperexcitability.
  • Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40
           in the brain and alleviates diabesity-associated learning and memory
           deficits in mice
    • Abstract: Publication date: Available online 6 July 2018Source: Neurobiology of DiseaseAuthor(s): Chandan Sona, Ajeet Kumar, Shalini Dogra, Boda Arun Kumar, Deepmala Umrao, Prem N. Yadav GPR40 (Free fatty acid receptor 1) has emerged as an important therapeutic target for diabetes. Several studies have demonstrated the association of comorbid psychiatric conditions with decreased n-3 polyunsaturated fatty acids, which may act as an agonist for GPR40. In this study, we for the first time provide evidence of reduced GPR40 signaling in the hippocampus and cortex which may be a critical underlying mechanism mediating cognitive deficits in diabesity (diabetes and obesity together). Specifically, we showed decreased GPR40 and brain-derived neurotrophic factor (BDNF) expression in the brain regions of high-fat-diet-induced obese and db/db mice. Next, we demonstrated that chronic treatment with docosahexaenoic acid (DHA) or the synthetic GPR40 agonist, GW9508, significantly alleviates cognitive functions in mice, which correlates with increased BDNF expression in the hippocampus. This supports the hypothesis that DHA improves cognitive function in diabesity via GPR40 agonism. We also showed that DHA specifically activates GPR40 and modulates BDNF expression in primary cortical neurons mediated by the extracellular receptor kinase (ERK) and P38-mitogen-activated protein kinase (MAPK) pathways. Finally, the central nervous system (CNS)-specific blockade of GPR40 signaling abrogated the memory potentiating effects of DHA, and induction of BDNF expression in the hippocampus. Thus, we provided evidence that DHA stimulation of GPR40 mediate some of DHA's beneficial effects in metabolic syndrome and identify GPR40 as a viable therapeutic target for the treatment of CNS-related comorbidities associated with diabesity.
  • Reduced axonal surface expression and phosphoinositide sensitivity in Kv7
           channels disrupts their function to inhibit neuronal excitability in Kcnq2
           epileptic encephalopathy
    • Abstract: Publication date: Available online 6 July 2018Source: Neurobiology of DiseaseAuthor(s): Eung Chang Kim, Jiaren Zhang, Weilun Pang, Shuwei Wang, Kwan Young Lee, John P. Cavaretta, Jennifer Walters, Erik Procko, Nien-Pei Tsai, Hee Jung Chung Neuronal Kv7/KCNQ channels are voltage-gated potassium channels composed of Kv7.2/KCNQ2 and Kv7.3/KCNQ3 subunits. Enriched at the axonal membrane, they potently suppress neuronal excitability. De novo and inherited dominant mutations in Kv7.2 cause early onset epileptic encephalopathy characterized by drug resistant seizures and profound psychomotor delay. However, their precise pathogenic mechanisms remain elusive. Here, we investigated selected epileptic encephalopathy causing mutations in calmodulin (CaM)-binding helices A and B of Kv7.2. We discovered that R333W, K526N, and R532W mutations located peripheral to CaM contact sites decreased axonal surface expression of heteromeric channels although only R333W mutation reduced CaM binding to Kv7.2. These mutations also altered gating modulation by phosphatidylinositol 4,5-bisphosphate (PIP2), revealing novel PIP2 binding residues. While these mutations disrupted Kv7 function to suppress excitability, hyperexcitability was observed in neurons expressing Kv7.2-R532W that displayed severe impairment in voltage-dependent activation. The M518 V mutation at the CaM contact site in helix B caused most defects in Kv7 channels by severely reducing their CaM binding, K+ currents, and axonal surface expression. Interestingly, the M518 V mutation induced ubiquitination and accelerated proteasome-dependent degradation of Kv7.2, whereas the presence of Kv7.3 blocked this degradation. Furthermore, expression of Kv7.2-M518V increased neuronal death. Together, our results demonstrate that epileptic encephalopathy mutations in helices A and B of Kv7.2 cause abnormal Kv7 expression and function by disrupting Kv7.2 binding to CaM and/or modulation by PIP2. We propose that such multiple Kv7 channel defects could exert more severe impacts on neuronal excitability and health, and thus serve as pathogenic mechanisms underlying Kcnq2 epileptic encephalopathy.Graphical abstractUnlabelled Image
  • Autophagy and mitophagy in ALS
    • Abstract: Publication date: Available online 5 July 2018Source: Neurobiology of DiseaseAuthor(s): Chantell S. Evans, Erika L.F. Holzbaur Amyotrophic lateral sclerosis (ALS) is a debilitating and incurable disease involving the loss of motor neurons and subsequent muscle atrophy. Genetic studies have implicated deficits in autophagy and/or mitophagy in the onset of the disease. Here we review recent progress in our understanding of the pathways for autophagy and mitophagy in neurons, and how these pathways may be affected by mutations in genes including DCTN1, OPTN, TBK1, VCP, and C9ORF72. We also discuss the implications of modulating autophagy in ALS, highlighting both the potential of the approach and the concerns raised by targeting this pathway as a therapeutic strategy in neurodegenerative disease.
  • Corrigendum to “Deficits in synaptic function occur at medial perforant
           path-dentate granule cell synapses prior to Schaffer collateral-CA1
           pyramidal cell synapses in the novel TgF344-Alzheimer's Disease Rat
           Model” [Neurobiology of Disease Volume 110, February 2018, Pages
    • Abstract: Publication date: Available online 2 July 2018Source: Neurobiology of DiseaseAuthor(s): Lindsey A. Smith, Lori L. McMahon
  • Neuroimaging markers of antipsychotic treatment response in schizophrenia:
           An overview of magnetic resonance imaging studies
    • Abstract: Publication date: Available online 25 June 2018Source: Neurobiology of DiseaseAuthor(s): Goda Tarcijonas, Deepak K. Sarpal Antipsychotic drugs are the primary treatment for psychosis, yet individual response to their administration remains variable. At present, no biological predictors of response exist to guide clinicians as they select treatments for patients, and our understanding of the neurobiology underlying the heterogeneity of outcomes remains limited. Magnetic Resonance Imaging (MRI) has been applied by numerous studies to examine the response to antipsychotic treatment, though a large gap remains between their results and our clinical practice. To advance patient care with precision medicine approaches, prior work must be accounted for and built upon with future studies. This review provides an overview of studies that relate treatment outcome to various MRI-related measures, including structural, spectroscopic, diffusion tensor, and functional imaging. Knowledge derived from these studies will be discussed along with future directions for the field.
  • CK2 inhibition confers functional protection to young and aging axons
           against ischemia by differentially regulating the CDK5 and AKT signaling
    • Abstract: Publication date: Available online 23 June 2018Source: Neurobiology of DiseaseAuthor(s): Chinthasagar Bastian, John Quinn, Ajai Tripathi, Danielle Aquila, Andrew McCray Ranjan Dutta, Selva Baltan, Sylvain Brunet White matter (WM) is injured in most strokes, which contributes to functional deficits during recovery. Casein kinase 2 (CK2) is a protein kinase that is expressed in brain, including WM. To assess the impact of CK2 inhibition on axon recovery following oxygen glucose deprivation (OGD), mouse optic nerves (MONs), which are pure WM tracts, were subjected to OGD with or without the selective CK2 inhibitor CX-4945. CX-4945 application preserved axon function during OGD and promoted axon function recovery when applied before or after OGD. This protective effect of CK2 inhibition correlated with preservation of oligodendrocytes and conservation of axon structure and axonal mitochondria. To investigate the pertinent downstream signaling pathways, siRNA targeting the CK2α subunit identified CDK5 and AKT as downstream molecules. Consequently, MK-2206 and roscovitine, which are selective AKT and CDK5 inhibitors, respectively, protected young and aging WM function only when applied before OGD. However, a novel pan-AKT allosteric inhibitor, ARQ-092, which targets both the inactive and active conformations of AKT, conferred protection to young and aging axons when applied before or after OGD. These results suggest that AKT and CDK5 signaling contribute to the WM functional protection conferred by CK2 inhibition during ischemia, while inhibition of activated AKT signaling plays the primary role in post-ischemic protection conferred by CK2 inhibition in WM independent of age. CK2 inhibitors are currently being used in clinical trials for cancer patients; therefore, our results will provide rationale for repurposing these drugs as therapeutic options for stroke patients by adding novel targets.
  • In search of antiepileptogenic treatments for post-traumatic epilepsy
    • Abstract: Publication date: Available online 22 June 2018Source: Neurobiology of DiseaseAuthor(s): Patricia G. Saletti, Idrish Ali, Pablo M. Casillas-Espinosa, Bridgette D. Semple, Christos Panagiotis Lisgaras, Solomon L. Moshé, Aristea S. Galanopoulou Post-traumatic epilepsy (PTE) is diagnosed in 20% of individuals with acquired epilepsy, and can impact significantly the quality of life due to the seizures and other functional or cognitive and behavioral outcomes of the traumatic brain injury (TBI) and PTE. There is no available antiepileptogenic or disease modifying treatment for PTE. Animal models of TBI and PTE have been developed, offering useful insights on the value of inflammatory, neurodegenerative pathways, hemorrhages and iron accumulation, calcium channels and other target pathways that could be used for treatment development. Most of the existing preclinical studies test efficacy towards pathologies of functional recovery after TBI, while a few studies are emerging testing the effects towards induced or spontaneous seizures. Here we review the existing preclinical trials testing new candidate treatments for TBI sequelae and PTE, and discuss future directions for efforts aiming at developing antiepileptogenic and disease-modifying treatments.
  • Alterations in cortical interneurons and cognitive function in
    • Abstract: Publication date: Available online 22 June 2018Source: Neurobiology of DiseaseAuthor(s): Samuel J. Dienel, David A. Lewis Certain clinical features of schizophrenia, such as working memory disturbances, appear to emerge from altered gamma oscillatory activity in the prefrontal cortex (PFC). Given the essential role of GABA neurotransmission in both working memory and gamma oscillations, understanding the cellular substrate for their disturbances in schizophrenia requires evidence from in vivo neuroimaging studies, which provide a means to link markers of GABA neurotransmission to gamma oscillations and working memory, and from postmortem studies, which provide insight into GABA neurotransmission at molecular and cellular levels of resolution. Here, we review findings from both types of studies which converge on the notions that 1) inhibitory GABA signaling in the PFC, especially between parvalbumin positive GABAergic basket cells and excitatory pyramidal cells, is required for gamma oscillatory activity and working memory function; and 2) disturbances in this signaling contribute to altered gamma oscillations and working memory in schizophrenia. Because the PFC is only one node in a distributed cortical network that mediates working memory, we also review evidence of GABA abnormalities in other cortical regions in schizophrenia.
  • A novel de novo HCN1 loss-of-function mutation in genetic generalized
           epilepsy causing increased neuronal excitability
    • Abstract: Publication date: Available online 21 June 2018Source: Neurobiology of DiseaseAuthor(s): Mattia Bonzanni, Jacopo C. DiFrancesco, Raffaella Milanesi, Giulia Campostrini, Barbara Castellotti, Annalisa Bucchi, Mirko Baruscotti, Carlo Ferrarese, Silvana Franceschetti, Laura Canafoglia, Francesca Ragona, Elena Freri, Angelo Labate, Antonio Gambardella, Cinzia Costa, Ilaria Rivolta, Cinzia Gellera, Tiziana Granata, Andrea Barbuti, Dario DiFrancesco
  • The neurobiological effects of repetitive head impacts in collision sports
    • Abstract: Publication date: Available online 21 June 2018Source: Neurobiology of DiseaseAuthor(s): Liane E. Hunter, Craig A. Branch, Michael L. Lipton It is now recognized that repetitive head impacts (RHI) in sport have the potential for long-term neurological impairments. In order to identify targets for intervention and/or pharmacological treatment, it is necessary to characterize the neurobiological mechanisms associated with RHI. This review aims to summarize animal and human studies that specifically address Blood Brain Barrier (BBB) dysfunction, abnormal neuro-metabolic and neuro-inflammatory processes as well as Tau aggregation associated with RHI in collision sports. Additionally, we examine the influence of physical activity and genetics on outcomes of RHI, discuss methodological considerations, and provide suggestions for future directions of this burgeoning area of research.
  • What is the therapeutic mechanism of pedunculopontine nucleus stimulation
           in Parkinson's disease'
    • Abstract: Publication date: Available online 19 June 2018Source: Neurobiology of DiseaseAuthor(s): Wesley Thevathasan, Elena Moro Pedunculopontine nucleus (PPN) deep brain stimulation (DBS) is an experimental treatment for Parkinson's disease (PD) which offers a fairly circumscribed benefit for gait freezing and perhaps balance impairment. The benefit on gait freezing is variable and typically incomplete, which may reflect that the clinical application is yet to be optimised or reflect a fundamental limitation of the therapeutic mechanism. Thus, a better understanding of the therapeutic mechanism of PPN DBS may guide the further development of this therapy. The available evidence supports that the PPN is underactive in PD due to a combination of both degeneration and excessive inhibition. Low frequency PPN DBS could enhance PPN network activity, perhaps via disinhibition. A clinical implication is that in some PD patients, the PPN may be too degenerate for PPN DBS to work. Reaction time studies report that PPN DBS mediates a very specific benefit on pre-programmed movement. This seems relevant to the pathophysiology of gait freezing, which can be argued to reflect impaired release of pre-programmed adjustments to locomotion. Thus, the benefit of PPN DBS on gait freezing could be akin to that mediated by external cues. Alpha band activity is a prominent finding in local field potential recordings from PPN electrodes in PD patients. Alpha band activity is implicated in the suppression of task irrelevant processes and thus the effective allocation of attention (processing resources). Attentional deficits are prominent in patients with PD and gait freezing and PPN alpha activity has been observed to drop out prior to gait freezing episodes and to increase with levodopa. This raises the hypothesis that PPN DBS could support or emulate PPN alpha activity and consequently enhance the allocation of attention. Although PPN DBS has not been convincingly shown to increase general alertness or attention, it remains possible that PPN DBS may enhance the allocation of processing resources within the motor system, or “motor attention”. For example, this could facilitate the ‘switching’ of motor state between continuation of pattern generated locomotion towards the intervention of pre-programmed adjustments. However, if the downstream consequence of PPN DBS on movement is limited to a circumscribed unblocking of pre-programmed movement, then this may have a similarly circumscribed degree of benefit for gait. If this is the case, then it may be possible to identify patients who may benefit most from PPN DBS. For example, those in whom pre-programmed deficits are the major contributors to gait freezing.
  • Electrophysiological biomarkers of epileptogenicity after traumatic brain
    • Abstract: Publication date: Available online 5 June 2018Source: Neurobiology of DiseaseAuthor(s): Piero Perucca, Gregory Smith, Cesar Santana-Gomez, Anatol Bragin, Richard Staba Post-traumatic epilepsy is the architype of acquired epilepsies, wherein a brain insult initiates an epileptogenic process culminating in an unprovoked seizure after weeks, months or years. Identifying biomarkers of such process is a prerequisite for developing and implementing targeted therapies aimed at preventing the development of epilepsy. Currently, there are no validated electrophysiological biomarkers of post-traumatic epileptogenesis. Experimental EEG studies using the lateral fluid percussion injury model have identified three candidate biomarkers of post-traumatic epileptogenesis: pathological high-frequency oscillations (HFOs, 80–300 Hz); repetitive HFOs and spikes (rHFOSs); and reduction in sleep spindle duration and dominant frequency at the transition from stage III to rapid eye movement sleep. EEG studies in humans have yielded conflicting data; recent evidence suggests that epileptiform abnormalities detected acutely after traumatic brain injury carry a significantly increased risk of subsequent epilepsy. Well-designed studies are required to validate these promising findings, and ultimately establish whether there are post-traumatic electrophysiological features which can guide the development of ‘antiepileptogenic’ therapies.
  • Minocycline attenuates brain injury and iron overload after intracerebral
           hemorrhage in aged female rats
    • Abstract: Publication date: Available online 5 June 2018Source: Neurobiology of DiseaseAuthor(s): Shuhui Dai, Ya Hua, Richard F. Keep, Nemanja Novakovic, Zhou Fei, Guohua Xi Brain iron overload is involved in brain injury after intracerebral hemorrhage (ICH). There is evidence that systemic administration of minocycline reduces brain iron level and improves neurological outcome in experimental models of hemorrhagic and ischemic stroke. However, there is evidence in cerebral ischemia that minocycline is not protective in aged female animals. Since most ICH research has used male models, this study was designed to provide an overall view of ICH-induced iron deposits at different time points (1 to 28 days) in aged (18-month old) female Fischer 344 rat ICH model and to investigate the neuroprotective effects of minocycline in those rats. According to our previous studies, we used the following dosing regimen (20 mg/kg, i.p. at 2 and 12 h after ICH onset followed by 10 mg/kg, i.p., twice a day up to 7 days). T2-, T2⁎-weighted and T2⁎ array MRI was performed at 1, 3, 7 and 28 days to measure brain iron content, ventricle volume, lesion volume and brain swelling. Immunohistochemistry was used to examine changes in iron handling proteins, neuronal loss and microglial activation. Behavioral testing was used to assess neurological deficits. In aged female rats, ICH induced long-term perihematomal iron overload with upregulated iron handling proteins, neuroinflammation, brain atrophy, neuronal loss and neurological deficits. Minocycline significantly reduced ICH-induced perihematomal iron overload and iron handling proteins. It further reduced brain swelling, neuroinflammation, neuronal loss, delayed brain atrophy and neurological deficits. These effects may be linked to the role of minocycline as an iron chelator as well as an inhibitor of neuroinflammation.
  • Big data sharing and analysis to advance research in post-traumatic
    • Abstract: Publication date: Available online 1 June 2018Source: Neurobiology of DiseaseAuthor(s): Dominique Duncan, Paul Vespa, Asla Pitkänen, Adebayo Braimah, Niina Lapinlampi, Arthur W. Toga We describe the infrastructure and functionality for a centralized preclinical and clinical data repository and analytic platform to support importing heterogeneous multi-modal data, automatically and manually linking data across modalities and sites, and searching content. We have developed and applied innovative image and electrophysiology processing methods to identify candidate biomarkers from MRI, EEG, and multi-modal data. Based on heterogeneous biomarkers, we present novel analytic tools designed to study epileptogenesis in animal model and human with the goal of tracking the probability of developing epilepsy over time.
  • Early seizures and temporal lobe trauma predict post-traumatic epilepsy: A
           longitudinal study
    • Abstract: Publication date: Available online 1 June 2018Source: Neurobiology of DiseaseAuthor(s): Meral A. Tubi, Evan Lutkenhoff, Manuel Buitrago Blanco, David McArthur, Pablo Villablanca, Benjamin Ellingson, Ramon Diaz-Arrastia, Paul Van Ness, Courtney Real, Vikesh Shrestha, Jerome Engel, Paul M. Vespa, EpiBioS4Rx Study Group Investigators, Denes Agoston, Alicia Au, Michael J. Bell, Tom Bleck, Craig Branch, Manuel Buitrago Blanco, Ross Bullock, Brian T. Burrows ObjectiveInjury severity after traumatic brain injury (TBI) is a well-established risk factor for the development of post-traumatic epilepsy (PTE). However, whether lesion location influences the susceptibility of seizures and development of PTE longitudinally has yet to be defined. We hypothesized that lesion location, specifically in the temporal lobe, would be associated with an increased incidence of both early seizures and PTE. As secondary analysis measures, we assessed the degree of brain atrophy and functional recovery, and performed a between-group analysis, comparing patients who developed PTE with those who did not develop PTE.MethodsWe assessed early seizure incidence (n = 90) and longitudinal development of PTE (n = 46) in a prospective convenience sample of patients with moderate-severe TBI. Acutely, patients were monitored with prospective cEEG and a high-resolution Magnetic Resonance Imaging (MRI) scan for lesion location classification. Chronically, patients underwent a high-resolution MRI, clinical assessment, and were longitudinally monitored for development of epilepsy for a minimum of 2 years post-injury.ResultsEarly seizures, occurring within the first week post-injury, occurred in 26.7% of the patients (n = 90). Within the cohort of subjects who had evidence of early seizures (n = 24), 75% had a hemorrhagic temporal lobe injury on admission. For longitudinal analyses (n = 46), 45.7% of patients developed PTE within a minimum of 2 years post-injury. Within the cohort of subjects who developed PTE (n = 21), 85.7% had a hemorrhagic temporal lobe injury on admission and 38.1% had early (convulsive or non-convulsive) seizures on cEEG monitoring during their acute ICU stay. In a between-group analysis, patients with PTE (n = 21) were more likely than patients who did not develop PTE (n = 25) to have a hemorrhagic temporal lobe injury (p 
  • Lysosome trafficking and signaling in health and neurodegenerative
    • Abstract: Publication date: Available online 30 May 2018Source: Neurobiology of DiseaseAuthor(s): Pearl P.Y. Lie, Ralph A. Nixon Lysosomes, single-membrane organelles defined by a uniquely strong acidic lumenal pH and high content of acid hydrolases, are the shared degradative compartments of the endocytic and autophagic pathways. These pathways, and especially lysosomes, are points of particular vulnerability in many neurodegenerative diseases. Beyond the role of lysosomes in substrate degradation, new findings have ascribed to lysosomes the leading role in sensing and responding to cellular nutrients, growth factors and cellular stress. This review aims to integrate recent concepts of basic lysosome biology and pathobiology as a basis for understanding neurodegenerative disease pathogenesis. Here, we discuss the newly recognized signaling functions of lysosomes and specific aspects of lysosome biology in neurons while re-visiting the classical defining criteria for lysosomes and the importance of preserving strict definitions. Our discussion emphasizes dynein-mediated axonal transport of maturing degradative organelles, with further consideration of their roles in synaptic function. We finally examine how distinctive underlying disturbances of lysosomes in various neurodegenerative diseases result in unique patterns of auto/endolysosomal mistrafficking. The rapidly emerging understanding of lysosomal trafficking and disruptions in lysosome signaling is providing valuable clues to new targets for disease-modifying therapies.
  • TFEB dysregulation as a driver of autophagy dysfunction in
           neurodegenerative disease: Molecular mechanisms, cellular processes, and
           emerging therapeutic opportunities
    • Abstract: Publication date: Available online 28 May 2018Source: Neurobiology of DiseaseAuthor(s): Constanza J. Cortes, Albert R. La Spada Two decades ago, the recognition of protein misfolding and aggregate accumulation as defining features of neurodegenerative disease set the stage for a thorough examination of how protein quality control is maintained in neurons and in other non-neuronal cells in the central nervous system (CNS). Autophagy, a pathway of cellular self-digestion, has emerged as especially important for CNS proteostasis, and autophagy dysregulation has been documented as a defining feature of neurodegeneration in Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Transcription factor EB (TFEB) is one of the main transcriptional regulators of autophagy, as it promotes the expression of genes required for autophagosome formation, lysosome biogenesis, and lysosome function, and it is highly expressed in CNS. Over the last 7 years, TFEB has received considerable attention and TFEB dysfunction has been implicated in the pathogenesis of numerous neurodegenerative disorders. In this review, we delineate the current understanding of how TFEB dysregulation is involved in neurodegeneration, highlighting work done on AD, PD, HD, X-linked spinal & bulbar muscular atrophy, and amyotrophic lateral sclerosis. Because TFEB is a central node in defining autophagy activation status, efforts at understanding the basis for TFEB dysfunction are yielding insights into how TFEB might be targeted for therapeutic application, which may represent an exciting opportunity for the development of a treatment modality with broad application to neurodegeneration.
  • Chaperone-mediated autophagy: Advances from bench to bedside
    • Abstract: Publication date: Available online 22 May 2018Source: Neurobiology of DiseaseAuthor(s): Wenming Li, Tiejian Nie, Haidong Xu, Jing Yang, Qian Yang, Zixu Mao Protein homeostasis or proteostasis is critical for proper cellular function and survival. It relies on the balance between protein synthesis and degradation. Lysosomes play an important role in degrading and recycling intracellular components via autophagy. Among the three types of lysosome-based autophagy pathways, chaperone-mediated autophagy (CMA) selectively degrades cellular proteins with KFERQ-like motif by unique machinery. During the past several years, significant advances have been made in our understanding of how CMA itself is modulated and what physiological and pathological processes it may be involved in. One particularly exciting discovery is how other cellular stress organelles such as ER signal to CMA. As more proteins are identified as CMA substrates, CMA function has been associated with an increasing number of important cellular processes, organelles, and diseases, including neurodegenerative diseases. Here we will summarize the recent advances in CMA biology, highlight ER stress-induced CMA, and discuss the role of CMA in diseases.
  • Contribution of induced pluripotent stem cell technologies to the
           understanding of cellular phenotypes in schizophrenia
    • Abstract: Publication date: Available online 3 May 2018Source: Neurobiology of DiseaseAuthor(s): Shabeesh Balan, Manabu Toyoshima, Takeo Yoshikawa Schizophrenia is one of the leading causes of disability among mental disorders, contributing to a substantial socioeconomic burden. Our understanding of the mechanisms of the pathogenesis of the disease has largely been limited by its inherent complexity imparted by the polygenicity and interactions with environmental factors. Since pathobiological events are initiated in the schizophrenic brain long before the onset of the psychotic manifestations, characterizing these processes is limited, mainly due to a lack of access to neuronal tissues. Induced pluripotent stem cell (iPSC) technologies have provided an unprecedented opportunity to establish pluripotent stem cells from patients with schizophrenia and differentiate them into neuronal lineage, enabling an in vitro recapitulation of the pathogenesis of the disease. Despite the inherent challenges, patient-derived iPSC studies of schizophrenia have been instrumental in unraveling the cellular and molecular phenotypes that might be involved in the biological causality. Here we review the literature and focus on studies that have utilized patient-derived iPSCs to model the pathogenesis of schizophrenia. We also discuss the challenges in modeling cellular phenotypes of schizophrenia.
  • Roles for neuronal and glial autophagy in synaptic pruning during
    • Abstract: Publication date: Available online 28 April 2018Source: Neurobiology of DiseaseAuthor(s): Ori J. Lieberman, Avery F. McGuirt, Guomei Tang, David Sulzer The dendritic protrusions known as spines represent the primary postsynaptic location for excitatory synapses. Dendritic spines are critical for many synaptic functions, and their formation, modification, and turnover are thought to be important for mechanisms of learning and memory. At many excitatory synapses, dendritic spines form during the early postnatal period, and while many spines are likely being formed and removed throughout life, the net number are often gradually “pruned” during adolescence to reach a stable level in the adult. In neurodevelopmental disorders, spine pruning is disrupted, emphasizing the importance of understanding its governing processes. Autophagy, a process through which cytosolic components and organelles are degraded, has recently been shown to control spine pruning in the mouse cortex, but the mechanisms through which autophagy acts remain obscure. Here, we draw on three widely studied prototypical synaptic pruning events to focus on two governing principles of spine pruning: 1) activity-dependent synaptic competition and 2) non-neuronal contributions. We briefly review what is known about autophagy in the central nervous system and its regulation by metabolic kinases. We propose a model in which autophagy in both neurons and non-neuronal cells contributes to spine pruning, and how other processes that regulate spine pruning could intersect with autophagy. We further outline future research directions to address outstanding questions on the role of autophagy in synaptic pruning.
  • The role of autophagy in acute brain injury: A state of flux'
    • Abstract: Publication date: Available online 26 April 2018Source: Neurobiology of DiseaseAuthor(s): Michael S. Wolf, Hülya Bayır, Patrick M. Kochanek, Robert S.B. Clark It is established that increased autophagy is readily detectable after various types of acute brain injury, including trauma, focal and global cerebral ischemia. What remains controversial, however, is whether this heightened detection of autophagy in brain represents a homeostatic or pathologic process, or an epiphenomenon. The ultimate role of autophagy after acute brain injury likely depends upon: 1) the degree of brain injury and the overall autophagic burden; 2) the capacity of individual cell types to ramp up autophagic flux; 3) the local redox state and signaling of parallel cell death pathways; 4) the capacity to eliminate damage associated molecular patterns and toxic proteins and metabolites both intra- and extracellularly; and 5) the timing of the pro- or anti-autophagic intervention. In this review, we attempt to reconcile conflicting studies that support both a beneficial and detrimental role for autophagy in models of acute brain injury.
  • Epileptogenesis, traumatic brain injury, and biomarkers
    • Abstract: Publication date: Available online 3 April 2018Source: Neurobiology of DiseaseAuthor(s): Jerome Engel Epilepsy is one of the most common brain disorders, causing serious disability and premature death worldwide. Approximately 1.2% of the U.S. population has active epilepsy, and 30 to 40% have seizures that do not respond to antiseizure drugs. There currently is no treatment available that prevents epilepsy following a potential epileptogenic insult, and the search for disease or syndrome modifying interventions for epilepsy is a high priority of neurobiological research. This requires better understanding of neuronal mechanisms underlying the development of epilepsy, and biomarkers of this process that would permit cost-effective drug discovery, and validation in clinical trials, for potential antiepileptogenic compounds. EpiBioS4Rx is an NIH-funded Center without Walls consisting of collaborative investigations in the United States, Europe, and Australia of traumatic brain injury in patients, and a standardized animal model, to identify biomarkers of epileptogenesis and to determine their ability to assess the effectiveness of potential antiepileptogenic agents. Successful completion of this project is expected to result in design of an economically feasible, full-scale clinical trial of at least one antiepileptogenic intervention.
  • Genetic enhancement of macroautophagy in vertebrate models of
           neurodegenerative diseases
    • Abstract: Publication date: Available online 3 April 2018Source: Neurobiology of DiseaseAuthor(s): Patrick Ejlerskov, Avraham Ashkenazi, David C. Rubinsztein Most of the neurodegenerative diseases that afflict humans manifest with the intraneuronal accumulation of toxic proteins that are aggregate-prone. Extensive data in cell and neuronal models support the concept that such proteins, like mutant huntingtin or alpha-synuclein, are substrates for macroautophagy (hereafter autophagy). Furthermore, autophagy-inducing compounds lower the levels of such proteins and ameliorate their toxicity in diverse animal models of neurodegenerative diseases. However, most of these compounds also have autophagy-independent effects and it is important to understand if similar benefits are seen with genetic strategies that upregulate autophagy, as this strengthens the validity of this strategy in such diseases. Here we review studies in vertebrate models using genetic manipulations of core autophagy genes and describe how these improve pathology and neurodegeneration, supporting the validity of autophagy upregulation as a target for certain neurodegenerative diseases.
  • Dysregulation of the autophagic-lysosomal pathway in Gaucher and
           Parkinson's disease
    • Abstract: Publication date: Available online 14 March 2018Source: Neurobiology of DiseaseAuthor(s): Caleb Pitcairn, Willayat Yousuf Wani, Joseph R. Mazzulli The finding that mutations in the Gaucher's Disease (GD) gene GBA1 are a strong risk factor for Parkinson's Disease (PD) has allowed for unique insights into pathophysiology centered on disruption of the autophagic-lysosomal pathway. Protein aggregations in the form of Lewy bodies and the effects of canonical PD mutations that converge on the lysosomal degradation system suggest that neurodegeneration in PD is mediated by dysregulation of protein homeostasis. The well-characterized clinical and pathological relationship between PD and the lysosomal storage disorder GD emphasizes the importance of dysregulated protein metabolism in neurodegeneration, and one intriguing piece of this relationship is a shared phenotype of autophagic-lysosomal dysfunction in both diseases. Translational application of these findings may be accelerated by the use of midbrain dopamine neuronal models derived from induced pluripotent stem cells (iPSCs) that recapitulate several pathological features of GD and PD. In this review, we discuss evidence linking autophagic dysfunction to the pathophysiology of GD and GBA1-linked parkinsonism and focus more specifically on studies performed recently in iPSC-derived neurons.
  • Neurophysiology of the pedunculopontine tegmental nucleus
    • Abstract: Publication date: Available online 7 March 2018Source: Neurobiology of DiseaseAuthor(s): F. Vitale, A. Capozzo, P. Mazzone, E. Scarnati The interest in the pedunculopontine tegmental nucleus (PPTg), a structure located in the brainstem at the level of the pontomesencephalic junction, has greatly increased in recent years because it is involved in the regulation of physiological functions that fail in Parkinson's disease and because it is a promising target for deep brain stimulation in movement disorders. The PPTg is highly interconnected with the main basal ganglia nuclei and relays basal ganglia activity to thalamic and brainstem nuclei and to spinal effectors. In this review, we address the functional role of the main PPTg outputs directed to the basal ganglia, thalamus, cerebellum and spinal cord. Together, the data that we discuss show that the PPTg may influence thalamocortical activity and spinal motoneuron excitability through its ascending and descending output fibers, respectively. Cerebellar nuclei may also relay signals from the PPTg to thalamic and brainstem nuclei. In addition to participating in motor functions, the PPTg participates in arousal, attention, action selection and reward mechanisms. Finally, we discuss the possibility that the PPTg may be involved in excitotoxic degeneration of the dopaminergic neurons of the substantia nigra through the glutamatergic monosynaptic input that it provides to these neurons.
  • Bottom-up gamma maintenance in various disorders
    • Abstract: Publication date: Available online 17 January 2018Source: Neurobiology of DiseaseAuthor(s): E. Garcia-Rill, S. Mahaffey, James R. Hyde, F.J. Urbano Maintained gamma band activity is a key element of higher brain function, participating in perception, executive function, and memory. The pedunculopontine nucleus (PPN), as part of the reticular activating system (RAS), is a major source of the “bottom-up” flow of gamma activity to higher regions. However, interruption of gamma band activity is associated with a number of neurological and psychiatric disorders. This review will focus on the role of the PPN in activating higher regions to induce arousal and descending pathways to modulate posture and locomotion. As such, PPN deep brain stimulation (DBS) can not only help regulate arousal and stepping, but continuous application may help maintain necessary levels of gamma band activity for a host of other brain processes. We will explore the potential future applications of PPN DBS for a number of disorders that are characterized by disturbances in gamma band maintenance.
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Tel: +00 44 (0)131 4513762
Fax: +00 44 (0)131 4513327
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