Project 3: Roles of Tau Levels, Sequence and Interactors in Neural Network Dysfunction of Alzheimer's Disease

项目 3：Tau 水平、序列和相互作用因子在阿尔茨海默病神经网络功能障碍中的作用

• 批准号: 10670346
• 负责人: Lennart Mucke
• 金额: $ 110.73万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10670346
• 关键词: Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease patient; Alzheimer' s disease risk; Amino Acid Substitution; Amyloid beta-Protein; Amyloid deposition; Antisense Oligonucleotides; Apolipoprotein E; Apolipoproteins; Behavioral; Brain; Brain Diseases; Cell Nucleus; Cells; Clinical; Cognitive deficits; Collaborations; Dementia; Disease; Etiology; Experimental Models; Frontotemporal Lobar Degenerations; Gene Expression; Genes; Gliosis; Heterozygote; Human; Impaired cognition; Intervention; Knock-in; Mediating; Modeling; Molecular; Mus; Mutation; Nerve Degeneration; Neuronal Dysfunction; Neurons; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pattern; Phenotype; Physiological; Protein Isoforms; Risk; Role; Senile Plaques; Synapses; Therapeutic; Variant; Wild Type Mouse; abeta accumulation; apolipoprotein E-4; cell type; early onset; experimental study; familial Alzheimer disease; gene product; genetic risk factor; insight; mouse model; mutant; network dysfunction; neural; neural network; novel; overexpression; pathogen; prevent; tau Proteins; tau mutation; transcriptomics

PROJECT 3 – SUMMARY Tau contributes to Alzheimer’s disease (AD) and many other brain diseases. However, it is uncertain how tau causes neuronal dysfunction and degeneration, in part because experimental models are not optimized to compare the relative pathogenicity of different tau species in disease-relevant contexts. Mutations in MAPT, the gene encoding tau, cause frontotemporal lobar degeneration (FTLD) instead of AD. In contrast, the rare A152T variant of tau increases risk for both types of diseases. These associations merit further exploration, especially as models expressing FTLD-mutant tau are widely used to study tau in AD and to develop novel AD treatments. Clinical AD onset is preceded by abnormal accumulations of amyloid-b (Ab) peptides in brain, and many AD patients have at least one apolipoprotein (apo) E4 allele, the most important genetic risk factor for AD. Therefore, we will generate new mouse models combining human Ab and apoE4 expression with near-physiological levels of human tau that is (1) wildtype, as in most AD patients, (2) carries the A152T substitution, which increases AD risk, or (3) bears the P301S mutation, which causes FTLD and is widely used in overexpression models. Comprehensive functional, pathological, and transcriptomic analyses of the new models, in collaboration with Projects 1, 2, and 4 and Core B, should yield new insights into differential effects of these tau species and their roles in the pathogenesis of dementia. We hypothesize that tau species that increase AD risk or cause FTLD differ in their effects on the integrity and function of neurons and neural networks, especially when combined with Aβ and apoE4. Until we know which forms of tau are most pathogenic in different conditions, the most pragmatic therapeutic approach to tau in our view is partial reduction of overall tau levels, which is well tolerated and has benefits in conventional models. We will therefore use tau-targeting antisense oligonucleotides (ASOs) to (1) determine whether reducing human tau can diminish neural network dysfunction, neurodegeneration and cognitive decline in models co-expressing human Ab and apoE4, (2) define the optimal timing for this intervention, and (3) reveal the most critical co-pathogenic mechanisms of tau. We hypothesize that ASO- mediated tau reduction will diminish not only tau pathology in one or more of the new models, but also synaptic deficits, neural network dysfunction, and cognitive deficits, even though it is unlikely to reduce amyloid deposition or plaque-associated microgliosis. This experiment should help determine when tau reduction must be initiated relative to the onset of cognitive deficits for it to have therapeutic benefits in AD-relevant contexts. Single- nucleus/single-cell transcriptomic analyses will be used to identify cell-type-specific gene expression changes and novel molecular and cellular mechanisms that may mediate pathogenic effects of tau or beneficial effects of tau reduction. These analyses will also help Projects 1 and 2 distinguish between pathogenic mechanisms of apoE4 and Ab that do or do not depend on tau and could identify novel molecular and cellular mechanisms that mediate tau sequence-specific effects in the absence or presence of AD-relevant co-pathogens.

项目 3 – 摘要 Tau 蛋白会导致阿尔茨海默病 (AD) 和许多其他脑部疾病，但目前尚不清楚 tau 蛋白如何导致。 导致神经功能障碍和退化，部分原因是实验模型没有针对 比较不同 tau 物种在疾病相关突变中的相对致病性。 编码 tau 的基因会导致额颞叶变性 (FTLD)，而不是 AD，相反，罕见的 A152T。 tau 蛋白变异会增加这两种疾病的风险，尤其是这些关联值得进一步探索。 表达 FTLD 突变 tau 的模型被广泛用于研究 AD 中的 tau 蛋白并开发新的 AD 治疗方法。 临床 AD 发病之前，大脑中淀粉样蛋白 - B (Ab) 肽异常积聚，并且许多 AD 患者至少有一种载脂蛋白 (apo) E4 等位基因，这是 AD 最重要的遗传风险因素。 我们将生成将人类 Ab 和 apoE4 表达与接近生理水平相结合的新小鼠模型 人类 tau 蛋白 (1) 野生型，如大多数 AD 患者，(2) 携带 A152T 取代，这会增加 AD 风险，或（3）携带P301S突变，导致FTLD并广泛用于过表达模型。 与以下机构合作，对新模型进行全面的功能、病理和转录组分析 项目 1、2 和 4 以及核心 B，应该会对这些 tau 物种及其差异效应产生新的见解。 我们捕获了增加 AD 风险或导致 FTLD 的 tau 蛋白物种。 它们对神经元和神经网络的完整性和功能的影响不同，尤其是组合时 直到我们知道哪种形式的 tau 在不同条件下致病性最强。 我们认为，实用的 tau 治疗方法是部分降低总体 tau 水平，这种方法具有良好的耐受性 因此，我们将使用 tau 靶向反义寡核苷酸 (ASO)。 (1) 确定减少人类 tau 蛋白是否可以减轻神经网络功能障碍、神经变性和 共表达人类 Ab 和 apoE4 的模型中的认知能力下降，(2) 定义了这种情况的最佳时机 干预，(3) 揭示 tau 最关键的共致病机制。 介导的 tau 蛋白减少不仅会减少一种或多种新模型中的 tau 蛋白病理学，还会减少突触 缺陷、神经网络功能障碍和认知缺陷，尽管它不太可能减少淀粉样蛋白沉积 或斑块相关的小胶质细胞增生，该实验应有助于确定何时必须开始减少 tau 蛋白。 相对于认知缺陷的发生，它在 AD 相关情况下具有治疗益处。 细胞核/单细胞转录组分析将用于识别细胞类型特异性基因表达变化 以及可能介导 tau 的致病作用或 tau 的有益作用的新分子和细胞机制 这些分析也将有助于项目 1 和 2 区分 tau 蛋白的致病机制。 apoE4 和 Ab 依赖或不依赖 tau，并且可以识别新的分子和细胞机制 在 AD 相关共病原体存在或不存在的情况下，介导 tau 序列特异性效应。