Differential vulnerability to tauopathy in Alzheimer's disease and Frontotemporal Lobe Dementia

阿尔茨海默病和额颞叶痴呆患者对 tau 蛋白病的易感性存在差异

基本信息

批准号：
10281586
负责人：
Karen Duff
金额：
$ 172.04万
依托单位：
UNIVERSITY COLLEGE LONDON
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10281586
关键词：
Differential vulnerability tauopathy Alzheimer disease

项目摘要

Project Summary Alzheimer’s Disease (AD) and Frontotemporal Lobe Degeneration spectrum diseases caused by tau (FTD- tau) are two neurodegenerative diseases that are characterized by accumulation of abnormal tau. It has been known for many years that tau does not accumulate in all cells in the brain despite the widespread expression of the tau gene. Some regions of the brain (and specific cell populations within them) are differentially vulnerable to accumulating pathological forms of tau. The reasons for this are unknown, and addressing this question is critical for AD and FTD, and also other neurodegenerative diseases showing selective vulnerability. We have observed that excitatory neurons (compared to inhibitory neurons) are especially vulnerable to tauopathy and, using a systems biology approach, have identified deficient tau homeostasis (proteostasis) as a likely mechanism. We now wish to extend these studies to a study on the impact of aging on tau homeostasis pathways in excitatory compared to inhibitory neurons, in human and mouse brain, and in a novel human-derived neuron model, testing one pathway (BAG3) that was implicated from the transcriptomics. Additionally, we will examine the selective vulnerability of neurons in patients with primary tauopathies associated with FTD. Lastly we will work with RNA datasets generated by Allen Institute to identify key pathway differences between excitatory and inhibitory neurons from the entorhinal cortex to begin to identify why excitatory and inhibitory cells might differ in their proteostasis capacity. These studies will explore the basis of selective vulnerability to tauopathy, generate well-characterized resources and potentially identify new disease causing pathways.

项目概要阿尔茨海默病 (AD) 和 tau 蛋白引起的额颞叶变性谱系疾病 (FTD- tau）是两种神经退行性疾病，其特征是异常 tau 蛋白的积累。多年来人们都知道，尽管 tau 蛋白广泛存在于大脑中，但它并没有在大脑的所有细胞中积累。 tau 基因的表达。不同程度地容易积累病理形式的 tau 蛋白，其原因尚不清楚，并且解决这个问题对于 AD 和 FTD 以及其他神经退行性疾病至关重要我们观察到兴奋性神经元（与抑制性神经元相比）具有选择性脆弱性。特别容易受到 tau 蛋白病的影响，并且利用系统生物学方法，已经发现了 tau 蛋白缺陷稳态（蛋白质稳态）作为一种可能的机制，我们现在希望将这些研究扩展到关于与抑制性神经元相比，衰老对人类和人类中兴奋性神经元 tau 稳态通路的影响小鼠大脑，并在一种新型的人源神经元模型中，测试了一条涉及的通路（BAG3）此外，我们将检查患者神经元的选择性脆弱性。最后，我们将使用 Allen 生成的 RNA 数据集。研究所确定内嗅兴奋性和抑制性神经元之间的关键通路差异皮层开始确定为什么兴奋性细胞和抑制性细胞的蛋白质稳态能力可能不同。这些研究将探索 tau 蛋白病选择性脆弱性的基础，产生特征良好的资源并可能确定新的致病途径。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

In vivo rate-determining steps of tau seed accumulation in Alzheimer's disease.

DOI：
10.1126/sciadv.abh1448
发表时间：
2021-10-29
期刊：
Science advances
影响因子：
13.6
作者：
Meisl G;Hidari E;Allinson K;Rittman T;DeVos SL;Sanchez JS;Xu CK;Duff KE;Johnson KA;Rowe JB;Hyman BT;Knowles TPJ;Klenerman D
通讯作者：
Klenerman D

Efficient Derivation of Excitatory and Inhibitory Neurons from Human Pluripotent Stem Cells Stably Expressing Direct Reprogramming Factors.