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1دورية أكاديمية
المؤلفون: Das, Melanie, Mao, Wenjie, Voskobiynyk, Yuliya, Necula, Deanna, Lew, Irene, Petersen, Cathrine, Zahn, Allie, Yu, Gui-Qiu, Yu, Xinxing, Smith, Nicholas, Sayed, Faten, Gan, Li, Paz, Jeanne, Mucke, Lennart
مصطلحات موضوعية: Alzheimers disease, Amyloid precursor protein, EEG, Epilepsy, Glia, Hyperexcitability, Microglia, Network dysfunction, Synapses, TREM2, Humans, Animals, Mice, Alzheimer Disease, Alleles, Seizures, Amyloid beta-Peptides, Disease Models, Animal, Plaque, Amyloid, Membrane Glycoproteins, Receptors, Immunologic
الوصف: The R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2) increases the risk of Alzheimers disease (AD). To investigate potential mechanisms, we analyzed knockin mice expressing human TREM2-R47H from one mutant mouse Trem2 allele. TREM2-R47H mice showed increased seizure activity in response to an acute excitotoxin challenge, compared to wildtype controls or knockin mice expressing the common variant of human TREM2. TREM2-R47H also increased spontaneous thalamocortical epileptiform activity in App knockin mice expressing amyloid precursor proteins bearing autosomal dominant AD mutations and a humanized amyloid-β sequence. In mice with or without such App modifications, TREM2-R47H increased the density of putative synapses in cortical regions without amyloid plaques. TREM2-R47H did not affect synaptic density in hippocampal regions with or without plaques. We conclude that TREM2-R47H increases AD-related network hyperexcitability and that it may do so, at least in part, by causing an imbalance in synaptic densities across brain regions.
وصف الملف: application/pdf
العلاقة: qt0r38b76h; https://escholarship.org/uc/item/0r38b76hTest
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2دورية أكاديمية
المؤلفون: Lindquist, Britta E, Timbie, Clare, Voskobiynyk, Yuliya, Paz, Jeanne T
مصطلحات موضوعية: Thalamus, Humans, Epilepsy, Generalized, Absence, Seizures, Absence epilepsy, Burst firing, Generalized spike-and-wave discharge, Genetic generalized epilepsy, Idiopathic generalized epilepsy, Oscillation, Neurosciences, Brain Disorders, Neurodegenerative, 1.1 Normal biological development and functioning, Underpinning research, Aetiology, 2.1 Biological and endogenous factors, Neurological, Clinical Sciences, Neurology & Neurosurgery
الوصف: Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can cause seizures that rapidly generalize and cause altered awareness and unconsciousness. Here, we review the most recent advances in our understanding of how thalamic activity is regulated and discuss the gaps in our understanding of the mechanisms of generalized epilepsy syndromes. Elucidating the role of the thalamus in generalized epilepsy syndromes may lead to new opportunities to better treat pharmaco-resistant generalized epilepsy by thalamic modulation and dietary therapy.
وصف الملف: application/pdf
العلاقة: qt43n7j8nh; https://escholarship.org/uc/item/43n7j8nhTest
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3دورية أكاديمية
المؤلفون: Davis, Skylar E, Cook, Anna K, Hall, Justin A, Voskobiynyk, Yuliya, Carullo, Nancy V, Boyle, Nicholas R, Hakim, Ahmad R, Anderson, Kristian M, Hobdy, Kierra P, Pugh, Derian A, Murchison, Charles F, McMeekin, Laura J, Simmons, Micah, Margolies, Katherine A, Cowell, Rita M, Nana, Alissa L, Spina, Salvatore, Grinberg, Lea T, Miller, Bruce L, Seeley, William W, Arrant, Andrew E
المصدر: Acta Neuropathologica Communications, vol 11, iss 1
مصطلحات موضوعية: Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Neurosciences, Biological Sciences, Frontotemporal Dementia (FTD), Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Brain Disorders, Rare Diseases, Dementia, Neurodegenerative, Alzheimer's Disease Related Dementias (ADRD), Aging, Alzheimer's Disease, 2.1 Biological and endogenous factors, Aetiology, Neurological, Mice, Animals, Frontotemporal Dementia, Pick Disease of the Brain, Progranulins, Cathepsin D, Frontotemporal Lobar Degeneration, Mutation, DNA-Binding Proteins, Transgenic, Lysosome, Progranulin, TDP-43
الوصف: Loss of function progranulin (GRN) mutations are a major autosomal dominant cause of frontotemporal dementia (FTD). Patients with FTD due to GRN mutations (FTD-GRN) develop frontotemporal lobar degeneration with TDP-43 pathology type A (FTLD-TDP type A) and exhibit elevated levels of lysosomal proteins and storage material in frontal cortex, perhaps indicating lysosomal dysfunction as a mechanism of disease. To investigate whether patients with sporadic FTLD exhibit similar signs of lysosomal dysfunction, we compared lysosomal protein levels, transcript levels, and storage material in patients with FTD-GRN or sporadic FTLD-TDP type A. We analyzed samples from frontal cortex, a degenerated brain region, and occipital cortex, a relatively spared brain region. In frontal cortex, patients with sporadic FTLD-TDP type A exhibited similar increases in lysosomal protein levels, transcript levels, and storage material as patients with FTD-GRN. In occipital cortex of both patient groups, most lysosomal measures did not differ from controls. Frontal cortex from a transgenic mouse model of TDP-opathy had similar increases in cathepsin D and lysosomal storage material, showing that TDP-opathy and neurodegeneration can drive these changes independently of progranulin. To investigate these changes in additional FTLD subtypes, we analyzed frontal cortical samples from patients with sporadic FTLD-TDP type C or Pick's disease, an FTLD-tau subtype. All sporadic FTLD groups had similar increases in cathepsin D activity, lysosomal membrane proteins, and storage material as FTD-GRN patients. However, patients with FTLD-TDP type C or Pick's disease did not have similar increases in lysosomal transcripts as patients with FTD-GRN or sporadic FTLD-TDP type A. Based on these data, accumulation of lysosomal proteins and storage material may be a common aspect of end-stage FTLD. However, the unique changes in gene expression in patients with FTD-GRN or sporadic FTLD-TDP type A may indicate distinct underlying lysosomal changes among FTLD ...
وصف الملف: application/pdf
العلاقة: qt5wf104d6; https://escholarship.org/uc/item/5wf104d6Test
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4دورية أكاديمية
المؤلفون: Cho, Frances S, Vainchtein, Ilia D, Voskobiynyk, Yuliya, Morningstar, Allison R, Aparicio, Francisco, Higashikubo, Bryan, Ciesielska, Agnieszka, Broekaart, Diede WM, Anink, Jasper J, van Vliet, Erwin A, Yu, Xinzhu, Khakh, Baljit S, Aronica, Eleonora, Molofsky, Anna V, Paz, Jeanne T
المصدر: Science Translational Medicine, vol 14, iss 652
مصطلحات موضوعية: Biomedical and Clinical Sciences, Neurosciences, Physical Injury - Accidents and Adverse Effects, Prevention, Epilepsy, Brain Disorders, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Good Health and Well Being, Animals, Astrocytes, Brain Injuries, COVID-19, Disease Models, Animal, GABA Plasma Membrane Transport Proteins, Inflammation, Mice, Polymers, Rodentia, SARS-CoV-2, Seizures, Thalamus, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
الوصف: Inflammatory processes induced by brain injury are important for recovery; however, when uncontrolled, inflammation can be deleterious, likely explaining why most anti-inflammatory treatments have failed to improve neurological outcomes after brain injury in clinical trials. In the thalamus, chronic activation of glial cells, a proxy of inflammation, has been suggested as an indicator of increased seizure risk and cognitive deficits that develop after cortical injury. Furthermore, lesions in the thalamus, more than other brain regions, have been reported in patients with viral infections associated with neurological deficits, such as SARS-CoV-2. However, the extent to which thalamic inflammation is a driver or by-product of neurological deficits remains unknown. Here, we found that thalamic inflammation in mice was sufficient to phenocopy the cellular and circuit hyperexcitability, enhanced seizure risk, and disruptions in cortical rhythms that develop after cortical injury. In our model, down-regulation of the GABA transporter GAT-3 in thalamic astrocytes mediated this neurological dysfunction. In addition, GAT-3 was decreased in regions of thalamic reactive astrocytes in mouse models of cortical injury. Enhancing GAT-3 in thalamic astrocytes prevented seizure risk, restored cortical states, and was protective against severe chemoconvulsant-induced seizures and mortality in a mouse model of traumatic brain injury, emphasizing the potential of therapeutically targeting this pathway. Together, our results identified a potential therapeutic target for reducing negative outcomes after brain injury.
وصف الملف: application/pdf
العلاقة: qt8hv41364; https://escholarship.org/uc/item/8hv41364Test
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5دورية أكاديمية
المؤلفون: Voskobiynyk, Yuliya
المصدر: All ETDs from UAB
مصطلحات موضوعية: Alzheimer's disease, BIN1, hyperexcitability, Tau, Doctor of Philosophy (PhD) Heersink School of Medicine, Medical Sciences
الوصف: Alzheimer’s disease (AD) is the leading neurodegenerative disorder that affects an astonishing 5.8 million Americans, a number projected to reach 14 million by the year 2050. While only about 1% of all AD cases are caused by mutations in APP, PSEN1, and PSEN2, the cause of sporadic AD remains unknown. Variations in several risk genes have been proposed to contribute to the development of sporadic AD cases. Since, currently, there are no disease-modifying therapies for families affected by AD and multiple anti-amyloid-beta therapies failed in clinical trials, determining how these risk genes contribute to the development of AD is crucial to identify new therapeutic avenues in AD. The second leading generic risk after APOE is BIN1, a direct interacting partner of Tau. Based on considerable preclinical data from AD models, genetically reducing either Tau or reducing its interaction with its binding partners has beneficial effects relevant to AD. Here, we describe BIN1’s role in neurons and how its interaction with Tau regulates network hyperexcitability through a voltage gated calcium channel complex. Furthermore, we characterized BIN1’s isoform-specific expression profiles in the human brain and its changes in the AD brains. Lastly, we determined that the loss of BIN1 in the brain leads to network hyperexcitability. Together, these data provide new insight into the potential role BIN1 plays in AD pathophysiology.
وصف الملف: application/pdf
العلاقة: https://digitalcommons.library.uab.edu/etd-collection/703Test; https://digitalcommons.library.uab.edu/context/etd-collection/article/1697/viewcontent/Voskobiynyk_uab_0005D_12984.pdfTest
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المؤلفون: Voskobiynyk, Yuliya, Roth, Jonathan, Cochran, J Nicholas, Rush, Travis, Carullo, Nancy, Mesina, Jacob, Waqas, Mohhamad, Vollmer, Rachael, Day, Jeremy, McMahon, Lori, Roberson, Erik
الوصف: Genome-wide association studies identified the BIN1 locus as a leading modulator of genetic risk in Alzheimer's disease (AD). One limitation in understanding BIN1's contribution to AD is its unknown function in the brain. AD-associated BIN1 variants are generally noncoding and likely change expression. Here, we determined the effects of increasing expression of the major neuronal isoform of human BIN1 in cultured rat hippocampal neurons. Higher BIN1 induced network hyperexcitability on multielectrode arrays, increased frequency of synaptic transmission, and elevated calcium transients, indicating that increasing BIN1 drives greater neuronal activity. In exploring the mechanism of these effects on neuronal physiology, we found that BIN1 interacted with L-type voltage-gated calcium channels (LVGCCs) and that BIN1–LVGCC interactions were modulated by Tau in rat hippocampal neurons and mouse brain. Finally, Tau reduction prevented BIN1-induced network hyperexcitability. These data shed light on BIN1's neuronal function and suggest that it may contribute to Tau-dependent hyperexcitability in AD. ; An excel file with the plate layout is uploaded. Funding provided by: National Institutes of HealthCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000002AwardTest Number: RF1AG059405Funding provided by: Alzheimer's AssociationCrossref Funder Registry ID: http://dx.doi.org/10.13039/100000957FundingTest provided by: Weston Brain InstituteCrossref Funder Registry ID: http://dx.doi.org/10.13039/100012479Test ; Multi electrode array cultures For 6-well multielectrode array recordings, neurons were plated at 100,000 per well in six-well MEA plates (ALA Scientific, ALAMEA-MEMMR5). For 48-well plate multielectrode array recordings, neurons were plated at 30,000 per well in 48-well MEA plates (Axion Biosystems, M768-tMEA-48B-5). BIN1 constructs and vectors A BIN1-mKate2 (GE Dharmacon, OHS5894-202501160) construct was developed to encode human BIN1 isoform 1 (593 AA, the major neuronal isoform) tagged with mKate2 (Evrogen, FP184, to ...
العلاقة: https://zenodo.org/communities/dryadTest; https://zenodo.org/record/3998336Test; https://doi.org/10.5061/dryad.rbnzs7h8zTest; oai:zenodo.org:3998336
الإتاحة: https://doi.org/10.5061/dryad.rbnzs7h8zTest
https://doi.org/10.7554/eLife.57354Test
https://zenodo.org/record/3998336Test -
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