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

• 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
• 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

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.

项目摘要 阿尔茨海默病(AD)和由tau引起的额颞叶退行性谱性疾病(FTD- Tau)是两种以异常tau积聚为特征的神经退行性疾病。它有 多年来一直知道，tau并不是在大脑的所有细胞中积聚，尽管广泛存在 Tau基因的表达。大脑的某些区域(以及其中的特定细胞群)是 对堆积的病理形式的tau具有不同的易感性。原因尚不清楚，而且 解决这个问题对AD和FTD以及其他神经退行性疾病表现出的 选择性漏洞。我们观察到兴奋性神经元(与抑制性神经元相比) 特别容易患上tau病，并利用系统生物学的方法发现了tau的缺陷 动态平衡(蛋白质平衡)是一种可能的机制。我们现在希望将这些研究扩展到关于 衰老对兴奋性神经元和抑制性神经元tau稳态通路的影响 小鼠大脑，并在一个新的人源性神经元模型中，测试一条与之相关的通路(BAG3) 从转录本中。此外，我们还将研究慢性阻塞性肺疾病患者神经元的选择性易损性。 与FTD相关的原发性肌萎缩症。最后，我们将使用Allen生成的RNA数据集 鉴定内嗅觉兴奋性神经元和抑制性神经元关键通路差异的研究所 大脑皮质开始识别为什么兴奋性细胞和抑制性细胞在蛋白稳定能力上可能不同。 这些研究将探索选择性易感性的基础，产生良好的特征 资源，并可能确定新的致病途径。

项目成果

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.

• DOI: 10.1002/cpz1.141
• 发表时间: 2021-06
• 期刊: Current protocols
• 作者: Song S;Ashok A;Williams D;Kaufman M;Duff K;Sproul A
• 通讯作者: Sproul A