Decoding the Multifactorial Etiology of Neural Network Dysfunction in Alzheimer's Disease

解读阿尔茨海默病神经网络功能障碍的多因素病因

• 批准号: 10525204
• 负责人: YADONG HUANG
• 金额: $ 9.17万
• 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/10525204
• 关键词: Address; Alleles; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Antisense Oligonucleotides; Bioinformatics; Brain; Brain Diseases; Cell Nucleus; Cells; Clinical; Collaborations; Data Set; Dementia; Development; Disease; Etiology; Experimental Models; Frontotemporal Lobar Degenerations; Gene Expression; Health; Human; Impaired cognition; MAPT gene; Mediating; Minority; Modeling; Molecular; Mutation; Nerve Degeneration; Neuronal Dysfunction; Neurons; Neurosciences; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Physiological; Research; Risk; Role; Science; Systems Biology; Talents; Therapeutic; Time; Training; Variant; abeta accumulation; apolipoprotein E-4; cell type; diverse data; experimental study; genetic risk factor; insight; mouse model; network dysfunction; neural network; neuromechanism; novel; novel therapeutic intervention; programs; tau Proteins; tau mutation; transcriptomics; working group

SUPPLEMENT – 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, Project 3 will generate new mouse models combining human Ab and apoE4 expression with near-physiological levels of human tau that is wildtype, as in most AD patients, or carries the A152T substitution, which increases AD risk. Comprehensive functional, pathological, and transcriptomic analyses of the new models, to be carried out 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. Project 3 will also investigate whether tau species that increase AD risk or cause FTLD differ in their effects on the integrity and functions of neurons and neural networks. 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 more conventional models. We will therefore use tau-targeting antisense oligonucleotides to reduce human tau levels in models co-expressing human Ab and apoE4. Single-nucleus/single-cell transcriptomic analyses will be used to identify cell-type-specific gene expression changes as well as novel molecular and cellular mechanisms that may mediate pathogenic effects of tau or beneficial effects of tau reduction. These analyses will help Projects 1 and 2 distinguish between pathogenic mechanisms of apoE4 and Ab that do or do not depend on tau. They could also identify novel molecular and cellular mechanisms that mediate tau sequence-specific effects. The requested supplement will allow a postdoctoral scholar from a background that is underrepresented in the health-related sciences to contribute to the experiments proposed in Project 3 and, at the same time, to benefit from training within the larger context of this AD-focused interdisciplinary program.

附件-摘要 Tau有助于阿尔茨海默病（AD）和许多其他脑部疾病。然而，目前还不确定tau 导致神经元功能障碍和变性，部分原因是实验模型没有优化， 比较不同tau物种在疾病相关背景下的相对致病性。MAPT突变， 编码tau蛋白的基因引起额颞叶变性（FTLD）而不是AD。相比之下，罕见的A152 T tau蛋白的变异增加了这两种疾病的风险。这些关联值得进一步探讨，特别是 作为表达FTLD-突变体tau的模型，广泛用于研究AD中的tau和开发新的AD治疗。 临床AD发作之前是脑中淀粉样蛋白-b（Ab）肽的异常积累，并且许多AD 患者至少有一个载脂蛋白（apo）E4等位基因，这是AD最重要的遗传危险因素。因此，我们认为， 项目3将产生新的小鼠模型，结合人Ab和apoE 4表达， 在大多数AD患者中，野生型或携带A152 T取代的人tau水平增加， AD风险。对新模型进行全面的功能、病理学和转录组学分析， 与项目1、2和4以及核心B合作，应该对以下方面的不同影响产生新的见解： 这些tau蛋白种类及其在痴呆症发病机制中的作用。项目3还将调查陶是否 增加AD风险或导致FTLD的物种在对神经元的完整性和功能的影响方面不同， 神经网络在我们知道哪些形式的tau在不同条件下致病性最强之前，最 我们认为，针对tau的务实治疗方法是部分降低总体tau水平，这是耐受性良好的 并且在更常规的模型中具有益处。因此，我们将使用靶向tau蛋白的反义寡核苷酸， 降低共表达人Ab和apoE 4的模型中的人tau水平。单核/单细胞 转录组学分析将用于鉴定细胞类型特异性基因表达变化以及新的 可能介导tau致病作用或tau有益作用的分子和细胞机制 还原这些分析将有助于项目1和项目2区分apoE 4的致病机制和 是否依赖于tau蛋白。他们还可以确定新的分子和细胞机制， 介导tau序列特异性作用。所要求的补充将允许博士后学者从一个 在健康相关科学中代表性不足的背景，以促进 项目3，同时受益于这一以广告为重点的 跨学科项目。