Seizure-induced enhancement of synaptic signaling regulating tau transmissibility in Alzheimer's Disease

癫痫发作诱导的突触信号增强调节阿尔茨海默病中 tau 蛋白的传递性

• 批准号: 10611518
• 负责人: Frances E Jensen
• 金额: $ 72.06万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611518
• 关键词: Acceleration; Address; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Anticonvulsants; Antiepileptic Agents; Attenuated; Autopsy; Behavioral; Blood specimen; Brain; Brain Mapping; Brain region; Cell Separation; Cells; Chronic; Complex; Dementia; Deposition; Disease; Disease Progression; Distant; Elements; Epilepsy; Epitopes; Exhibits; FOS gene; FRAP1 gene; Fluorescence Microscopy; Gene Expression; Generations; Hippocampus; Human; Hyperactivity; Immediate-Early Genes; Impaired cognition; Incidence; Label; Late Effects; Levetiracetam; Light; Maps; Measures; Mediating; Metabolism; Methods; Modification; Molecular; Mus; Nerve Degeneration; Neurons; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Pentylenetetrazole; Persons; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Positron-Emission Tomography; Process; Proteins; Recording of previous events; Seizures; Senile Plaques; Severities; Signal Pathway; Signal Transduction; Sirolimus; Synapses; Synaptic Transmission; Synaptic Vesicles; Tamoxifen; Tauopathies; Testing; Therapeutic Effect; Tissue-Specific Gene Expression; Treatment Efficacy; Western Blotting; amyloid pathology; behavior test; brain tissue; clinical biomarkers; comorbidity; comparison control; dementia risk; efficacy testing; high risk; human tissue; hyperphosphorylated tau; inhibitor; innovation; interest; mind control; mouse model; neuron loss; neuropathology; neurotransmission; novel; novel therapeutic intervention; pre-clinical; protein expression; spatiotemporal; targeted treatment; tau Proteins; tau aggregation; tau expression; tau mutation; tau-protein kinase; transcriptome; transcriptome sequencing; transmission process; uptake; vesicular release

Abstract Alzheimer’s Disease (AD) neuropathology is largely driven by two pathological AD proteins, tau, and ß-amyloid (Aß), both of which induce neuronal hyperexcitability and are thought to play a role in the high comorbidity between AD and epilepsy. Tau load and its regional brain distribution correlate more closely with cognitive decline than amyloid plaque deposition in both AD and epilepsy patients, making tau an attractive target for disease modification in both conditions. AD patients have an increased incidence of epilepsy compared to non-AD patients, and we recently showed that kindled seizures can exacerbate amyloid pathology, mediated by the mammalian target of rapamycin complex 1 (mTORC1) activation in an AD mouse model. To address how neuronal hyperactivity can increase AD pathology, we propose to use a tau seeding approach using two novel AD mice models to determine the effects of later seizures on the spatiotemporal accumulation of pathologic tau. We will also test the hypothesis that tau transmissibility in AD occurs through synaptic activation by adapting a method to permanently label cells activated by kindled seizures following tau seeding. This will allow us to measure the levels and spatial and temporal distribution of tau and AD pathology throughout the entire brain, as well as gene and protein expression at single neuron level. We will also utilize human brain tissue from AD patients with and without a seizure history, and controls, to validate molecular changes observed in the mouse models. Finally, given our prior observations regarding the therapeutic effects of rapamycin, and the hypothesis that tau accumulation and transmission is accelerated by seizures, we will use the two tau seeding mouse models to assess the therapeutic efficacy of post-seizure chronic treatment with the mTORC1 inhibitor rapamycin or the antiseizure drug levetiracetam in attenuating AD progression.

摘要