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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos 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

项目摘要

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.

补充-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。项目 3 将产生将人类 Ab 和 apoE4 表达与近生理学相结合的新小鼠模型与大多数 AD 患者一样，野生型人类 tau 水平，或携带 A152T 取代，这会增加 AD风险。对新模型进行全面的功能、病理和转录组分析。与项目 1、2、4 和核心 B 合作，应该会对不同影响产生新的见解这些 tau 蛋白物种及其在痴呆发病机制中的作用项目 3 还将研究 tau 蛋白是否存在。增加 AD 风险或导致 FTLD 的物种对神经元完整性和功能的影响不同直到我们知道哪种形式的 tau 蛋白在不同条件下最具致病性为止。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 靶向反义寡核苷酸来进行研究。降低共表达人 Ab 和 apoE4 的模型中的人 tau 水平。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这些分析将有助于项目 1 和 2 区分 apoE4 和 apoE4 的致病机制。他们还可以识别依赖或不依赖 tau 的新分子和细胞机制。介导 tau 序列特异性效应。健康相关科学中代表性不足的背景有助于为中提出的实验做出贡献项目 3，同时从这个以 AD 为中心的更大背景下的培训中受益跨学科计划。