Tau-mediated synaptic dysfunction in age-related neurodegenerative diseases
Document text
Principal Investigator: Audrey Weber Organization: UNIVERSITY OF ALABAMA AT BIRMINGHAM Fiscal Year: 2024 Award: $40,708 Funding agency: National Institute on Aging Neurofibrillary tangles (NFTs) of the microtubule-associated protein tau are a universal feature of the aging brain. The extent of tau pathology throughout the brain correlates with both synapse loss and severity of cognitive impairment in age-related tauopathies. The ability to maintain cognitive function with a brain accumulating NFTs relies on the preservation and maintenance of synaptic networks. Therefore, understanding the mechanism by which tau contributes to network and synapse vulnerability is critical for developing preventative therapeutics. The goal of this proposal is to determine the cellular mechanism(s) by which pathologic tau drives neuronal network dysfunction. The experiments proposed in this application will uncover these mechanisms and provide intellectual and technical training for a successful transition into a postdoctoral position. The F99 phase (Aim 1) will test mechanistic cell biological hypotheses to better define how abnormal tau accumulation induces synaptic dysfunction, while providing opportunity to develop intricate experimental design and execution skills through cutting-edge biochemistry, microscopy, and electrophysiology techniques. The K00 phase (Aim 2) will build upon the F99 studies with computational strategies to integrate proteomics data from humans and experimental models to identify co-existing molecular changes that are highly relevant to age-related tauopathies. Terms: <AD dementia><Action Potentials><Affect><Affinity><Age><Aging><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><Axon><Biochemical><Biochemistry><Biologic Models><Biological><Biological Chemistry><Biological Models><Body Tissues><Brain><Brain Nervous System><Brain region><Cell Body><Cell model><Cells><Cellular biology><Cellular model><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Communities><Data><Dendrites><Dendritic Spines><Disease><Disorder><Disturbance in cognition><Dysfunction><Electrophysiology><Electrophysiology (science)><Encephalon><Entorhinal Area><Event><Exhibits><Experimental Designs><Experimental Models><Exposure to><Functional disorder><Glutamate Receptor><Goals><Human><Impaired cognition><Investigators><Link><MAPT gene><MAPT protein><MT-bound tau><MTBT1><Maintenance><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Mediating><Memory><Methods><Micro-tubule><Microscopy><Microtubules><Model System><Modeling><Modern Man><Molecular><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocyte><Neurofibrillary Tangles><Neuron Degeneration><Neurons><Neurophysiology / Electrophysiology><Pathologic><Pathology><Pathway interactions><Patients><Phase><Phenotype><Physiopathology><Population><Position><Positioning Attribute><Postdoc><Postdoctoral Fellow><Primary Senile Degenerative Dementia><Process><Proteins><Proteome><Proteomics><Research><Research Associate><Research Personnel><Researchers><Sampling><Severities><Signal Pathway><Specificity><Spinal Column><Spine><Structure><Synapses><Synaptic><Tauopathies><Techniques><Temporal Lobe><Testing><Therapeutic><Tissues><Training><Universities><Validation><Vertebral column><Work><abnormal tau><abnormally aggregated tau protein><age associated><age associated neurodegeneration><age associated neurodegenerative disease><age associated neurodegenerative disorder><age correlated><age dependent><age dependent neurodegeneration><age dependent neurodegenerative condition><age dependent neurodegenerative disease><age dependent neurodegenerative disorder><age linked><age related><age related neurodegeneration><age specific><age-driven neurodegenerative disorders><age-related neurodegenerative disease><age-related neurodegenerative disorder><aged brain><ages><aging associated><aging associated neurodegeneration><aging associated neurodegenerative disease><aging brain><aging related><aging related neurodegeneration><aging related neurodegenerative disease><aging related neurodegenerative disorder><backbone><biologic><cell biology><cell type><cognitive dysfunction><cognitive function><cognitive loss><cohort><dendrite spine><density><disease model><disorder model><electrophysiological><entorhinal cortex><experiment><experimental research><experimental study><experiments><filamentous tau inclusion><human data><human disease><human model><interest><microtubule associated protein tau><microtubule associated protein tau aggregation><microtubule associated protein tau deposit><microtubule associated protein tau mutation><microtubule bound tau><microtubule-associated protein tau><microtubule-associated protein tau mutation><microtubule-bound tau><model of human><morphometry><mouse model><multi-electrode arrays><multielectrode arrays><murine model><mutant tau><mutation in microtubule associated protein tau><mutation in microtubule-associated protein tau><natural aging><network dysfunction><neural cell body><neural degeneration><neurodegeneration><neurodegenerative><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neurological degeneration><neuronal><neuronal cell body><neuronal degeneration><neuropathologic tau><neuropathological tau><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><normal aging><normative aging><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><paired helical filament of tau><pathogenic tau><pathogenic tau gene mutation><pathological change in tau><pathophysiology><pathway><post-doc><post-doctoral><post-doctoral trainee><postsynaptic><pre-clinical><preclinical><preservation><primary degenerative dementia><religious order study><research associates><self-aggregate tau><senile dementia of the Alzheimer type><skills><soma><success><synapse><tangle><tau><tau PHF><tau Proteins><tau abnormality><tau accumulation><tau aggregate><tau aggregation><tau associated neurodegeneration><tau associated neurodegenerative process><tau factor><tau fibrillization><tau filament><tau induced neurodegeneration><tau intronic mutation><tau mediated neurodegeneration><tau mutation><tau neurodegenerative disease><tau neurofibrillary tangle><tau neuropathology><tau oligomer><tau paired helical filament><tau pathological change><tau polymerization><tau-tau interaction><tauopathic neurodegenerative disorder><tauopathy><temporal cortex><therapeutic target><validations><τ Proteins><τ aggregation><τ mutation>