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TDP-43 in Alzheimer's disease

TDP-43 在阿尔茨海默病中的作用

基本信息

批准号：
10626094
负责人：
Nicole Faron Liachko
金额：
$ 53.02万
依托单位：
SEATTLE INST FOR BIOMEDICAL/CLINICAL RES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10626094
关键词：
Acceleration Affect Aging Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease patient Amyloid beta-Protein Amyotrophic Lateral Sclerosis Autopsy Behavioral Biological Assay Biology Brain Brain region Caenorhabditis elegans Code Cognitive Data Dementia Disease Exhibits Foundations Frontotemporal Lobar Degenerations Functional disorder Future Gene Expression Gene Expression Profile Genes Genetic Genetic Transcription Goals Human Impaired cognition Individual Inherited Intervention Maps Modeling Mutation Nerve Degeneration Nervous System Neurodegenerative Disorders Neurofibrillary Tangles Neuronal Dysfunction Neurons Neurotransmitters Outcome Pathologic Pathology Pathway interactions Patients Persons Phenotype Process Proteins RNA RNA interference screen Resistance Role Senile Plaques Stress Surveys TDP-43 aggregation Testing Therapeutic Intervention Toxic effect Transgenes Transgenic Organisms Work brain tissue cerebral atrophy comorbidity experience frontotemporal lobar dementia amyotrophic lateral sclerosis hippocampal sclerosis in vivo loss of function mutation model organism nervous system disorder neuroimaging neuropathology neurotoxic neurotoxicity new therapeutic target overexpression protein TDP-43 protein aggregation protein distribution protein expression proteostasis proteotoxicity resilience response synergism tau Proteins tau aggregation therapeutic development transcriptome transcriptome sequencing transcriptomics

项目摘要

Alzheimer’s disease, a severe progressive neurodegenerative disease of aging and the most common form of dementia, affects an estimated 30 million people worldwide. Pathologically, Alzheimer’s disease is defined by the presence of both amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau in disease affected brain regions. However, 30-57% of Alzheimer’s disease patients also exhibit TDP-43 aggregates as an additional co-pathology. The presence of TDP-43 pathology in Alzheimer’s disease correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. Given the recent recognition of TDP-43 as a frequent co- pathology in Alzheimer’s disease, understanding its contribution to neurodegenerative disease processes and potential synergies with other pathological disease-promoting proteins is a critical need in the field. Recent work using C. elegans found that co-expressed tau and TDP-43 leads to increased neurotoxicity and pathological protein accumulation. Building on this foundation, the proposed Aims will develop and utilize new tractable models of co-expressed tau and TDP-43 in order to understand the biology underlying their toxicity. Aim 1 will define consequences of low or regulatable levels of co-expressed tau and TDP-43 using behavioral and neuroimaging assays, and test relationships between tau and TDP-43. Aims 2 and 3 will employ RNA sequencing to reveal gene expression underlying comorbid tau and TDP-43 through aging in simple models, and in human post-mortem brain tissue from patients with Alzheimer’s disease with TDP-43 pathology. Candidates nominated from transcriptomic approaches will be tested for functional roles in tau and TDP-43 synergistic proteinopathy using genetic and transgenic approaches. This work will characterize mechanisms underlying tau and TDP-43 neurotoxicity in Alzheimer’s disease and identify new therapeutic targets and strategies. Completion of this project will significantly advance understanding Alzheimer’s disease with comorbid TDP-43, and provide the groundwork for future therapeutic development targeting TDP-43 in Alzheimer’s disease.

阿尔茨海默病，一种严重的进行性神经退行性疾病，是老年痴呆症的最常见形式。痴呆症影响着全世界约3000万人。在病理学上，阿尔茨海默病的定义是淀粉样蛋白斑块由β淀粉样蛋白（Aβ）和神经纤维缠结组成，在受疾病影响的大脑区域含有tau蛋白。然而，30-57%的阿尔茨海默病患者也表现出TDP-43聚集体作为额外的共同病理。TDP-43病理学的存在，阿尔茨海默病与海马硬化、更严重的脑萎缩、更严重的认知功能障碍、以及更快的认知能力下降。鉴于最近认识到TDP-43是一种常见的共同体，阿尔茨海默病的病理学，了解其对神经退行性疾病过程的贡献，与其它病理性疾病促进蛋白的潜在协同作用是本领域的关键需求。最近使用C. elegans发现共表达的tau和TDP-43导致神经毒性增加，病理性蛋白质积累。在此基础上，拟议的目标将开发和利用新的共表达tau和TDP-43的易处理模型，以了解其毒性的生物学基础。目的1将使用行为学方法定义低水平或可调节水平的共表达tau和TDP-43的后果。和神经成像分析，并测试tau和TDP-43之间的关系。目标2和3将使用RNA 测序以揭示在简单模型中通过老化导致共病tau和TDP-43的基因表达，和来自具有TDP-43病理学的阿尔茨海默病患者的人类死后脑组织中。从转录组学方法提名的候选人将被测试在tau和TDP-43中的功能作用使用遗传和转基因方法的协同蛋白质病。这项工作将描述机制阿尔茨海默病中潜在的tau和TDP-43神经毒性，并确定新的治疗靶点，战略布局该项目的完成将大大促进对阿尔茨海默病的了解，共病TDP-43，并为将来靶向TDP-43的治疗开发奠定基础。老年痴呆症