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

项目摘要 阿尔茨海默病（AD）和由tau蛋白引起的额颞叶变性谱疾病（FTD-tau） 是两种以异常tau蛋白积累为特征的神经退行性疾病。人们已经知道 多年来，尽管tau蛋白广泛表达，但tau蛋白并没有在大脑的所有细胞中积累。 tau基因。大脑的某些区域（以及其中的特定细胞群）对 积累病理形式的tau蛋白。其原因尚不清楚，解决这个问题至关重要 AD和FTD，以及其他表现出选择性脆弱性的神经退行性疾病。我们观察到 兴奋性神经元（与抑制性神经元相比）特别容易受到tau蛋白病的影响， 系统生物学方法，已经鉴定出缺乏tau稳态（蛋白稳态）作为可能的机制。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中tau稳态通路的影响的研究。 与抑制性神经元相比，在人类和小鼠大脑中，以及在一种新的人类衍生神经元模型中， 一个途径（BAG 3）与转录组学有关。此外，我们将研究选择性 FTD相关原发性tau蛋白病患者的神经元易损性。最后，我们将研究RNA 艾伦研究所生成的数据集，以确定兴奋性和抑制性之间的关键通路差异 从内嗅皮层到皮层的神经元开始识别为什么兴奋性细胞和抑制性细胞在它们的 蛋白抑制能力这些研究将探索对tau蛋白病的选择性易感性的基础， 充分表征的资源，并有可能确定新的致病途径。

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.