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（FTD-1）引起的额颞叶变性谱疾病 tau）是两种以异常tau的积累为特征的神经变性疾病。它有 多年来，人们已经知道，尽管tau蛋白在大脑中广泛存在，但它并不积累在所有细胞中。 tau基因的表达。大脑的某些区域（以及其中的特定细胞群） 对累积的病理形式的tau有不同的脆弱性。原因不明， 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， 选择性脆弱性我们已经观察到，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，并且使用系统生物学方法， 体内平衡（蛋白质平衡）作为可能的机制。我们现在希望将这些研究扩展到对 与抑制性神经元相比，在人类中老化对兴奋性神经元中tau稳态通路的影响， 小鼠脑，并在一种新的人类来源的神经元模型，测试一个途径（BAG 3），这是牵连 从转录组学上。此外，我们将研究神经元的选择性脆弱性， FTD相关原发性tau蛋白病。最后，我们将使用艾伦生成的RNA数据集 研究所确定兴奋性和抑制性神经元之间的关键通路差异，从内嗅 皮质开始，以确定为什么兴奋性和抑制性细胞可能在其蛋白质稳态能力不同。 这些研究将探索对tau蛋白病的选择性易感性的基础，产生良好表征的 资源和潜在的确定新的疾病引起的途径。

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.