Regulation of human tau expression and tauopathy by alpha-synuclein

α-突触核蛋白对人类 tau 蛋白表达和 tau 蛋白病的调节

基本信息

批准号：
10464632
负责人：
MICHAEL K LEE
金额：
$ 76.48万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10464632
关键词：
Ablation Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Attenuated Autophagocytosis Biology Cell Culture System Chronic Clinical Cognitive Cognitive deficits Coupling Data Defect Degradation Pathway Dementia Deposition Disease Progression Frontotemporal Dementia Human Impaired cognition Knowledge Lewy Body Dementia Link Mediating Memory Loss Memory impairment Modeling Mus Neurons Onset of illness PHF-1 Parkinson Disease Pathologic Pathology Pathway interactions Prosencephalon Protein Isoforms Proteins Regulation Reporting Role SNCA gene Series Surveys Synapses Synaptic Vesicles Syndrome System Tauopathies Testing Therapeutic Transgenic Mice Ubiquitin Viral Vector Wild Type Mouse alpha synuclein cognitive function conditional knockout delivery vehicle design endoplasmic reticulum stress excitatory neuron genetic approach hyperphosphorylated tau in vivo mouse model multicatalytic endopeptidase complex neuropathology novel overexpression pre-clinical prevent protein degradation synaptic function synuclein tau Proteins tau aggregation tau expression tau-1 therapeutic evaluation β-amyloid burden

项目摘要

Project Summary Mixed neuropathologies are the most common cause of the clinical syndrome of dementia, including Alzheimer's disease (AD), Lewy body dementia (LBD) and frontotemporal dementia (FTD). Exploiting novel constitutive and conditional knockout lines as well as transgenic mouse lines, we now propose a series of genetic approaches designed to uncover key knowledge gaps linking alpha-synuclein (αSyn) and tau biology, pathologies and their relationships to synaptic and cognitive function. Leveraging emerging evidence from independent groups including our own, we will test the central hypothesis that αSyn expression, independent of αSyn pathology, may impact the biology tau and/or tau-dependent pathology. In the light of novel findings reported in the preliminary results, we will i) test the hypothesis that αSyn regulates human tau selectively, but not mouse tau, ii) test the prediction that constitutive ablation of the SNCA gene encoding αSyn alleviates tau pathology and tau-induced cognitive deficits in a model of tauopathy, iii) test the hypothesis that conditional ablation of SNCA in forebrain excitatory neurons alleviates tau pathology and tau-induced cognitive deficits in a model of tauopathy, thereby providing a preclinical proof-of-principle that targeting this αSyn/tau coupling might be therapeutically beneficial in the context of FTD and LBD.

项目概要混合神经病理学是痴呆症临床综合征的最常见原因，包括阿尔茨海默病疾病（AD）、路易体痴呆（LBD）和额颞叶痴呆（FTD）。条件敲除系以及转基因小鼠系，我们现在提出了一系列遗传方法旨在揭示 α-突触核蛋白 (αSyn) 和 tau 生物学、病理学及其相关的关键知识差距利用来自独立群体的新证据。包括我们自己的，我们将检验中心假设，即独立于 αSyn 病理学的 αSyn 表达可能会根据初步报告中的新发现，影响 tau 生物学和/或 tau 依赖性病理学。结果，我们将 i) 检验 αSyn 选择性调节人类 tau 而不是小鼠 tau 的假设，ii) 检验预测编码 αSyn 的 SNCA 基因的组成型消融可减轻 tau 病理学和 tau 诱导的 tau蛋白病模型中的认知缺陷，iii)检验前脑中SNCA的条件消融的假设兴奋性神经元可减轻 tau 蛋白病模型中的 tau 蛋白病理学和 tau 蛋白诱导的认知缺陷，从而提供临床前原理验证，表明针对这种 αSyn/tau 偶联可能具有治疗益处在 FTD 和 LBD 的背景下。