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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：
10622614
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/10622614
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.

项目摘要混合神经病理是痴呆临床综合征的最常见原因，包括阿尔茨海默氏症阿尔茨海默病(AD)、路易体痴呆(LBD)和额颞部痴呆(FTD)。开发新的构成和对于条件基因敲除系和转基因小鼠系，我们现在提出了一系列的遗传方法旨在揭示α-突触核蛋白(α-Syn)和tau生物学、病理学及其之间的关键知识差距与突触和认知功能的关系。利用来自独立团体的新证据包括我们自己在内，我们将测试核心假设，即αsyn的表达独立于αsyn病理，可能影响生物学上的tau和/或tau依赖的病理。根据初步报告中报告的新发现结果，我们将i)检验αsyn选择性调节人tau而不是鼠tau的假设，ii)检验预测编码αSyn的SNCA基因的结构性消融可减轻tau病理和tau诱导的颈椎病模型中的认知缺陷，III)验证了前脑条件消融SNCA的假设兴奋性神经元减轻tau病变和tau诱导的认知障碍，从而提供一项临床前原则证明，靶向α同步蛋白/tau偶联可能在治疗上是有益的在FTD和LBD的背景下。