权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
9765938
负责人：
Karen Duff
金额：
$ 39.1万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
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 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9765938
关键词：
Address Affect Age Aging Alzheimer&apos s Disease Amyloid Autophagocytosis BAG3 gene Biological Models Brain Brain region Candidate Disease Gene Cell Line Cell model Cells Collaborations Correlative Study Data Set Disease Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional disorder Gene Cluster Gene Expression Genes Glutamates Goals Homeostasis Human Immunohistochemistry In Vitro Institutes Label Location Mediating Modeling Molecular Molecular Chaperones Mus Mutagenesis Nerve Degeneration Neurodegenerative Disorders Neuroglia Neurons Pathogenesis Pathologic Pathologic Processes Pathology Pathway interactions Patients Population Property RNA Regulation Regulator Genes Reporter Resources Science Specificity Stem cells Symptoms System Systems Analysis Systems Biology Tauopathies Techniques Testing Ubiquitin Vacuole Vulnerable Populations Work age related cell type entorhinal cortex excitatory neuron functional disability in vivo inhibitory neuron interest multicatalytic endopeptidase complex neocortical novel proteostasis tau Proteins tau aggregation tau expression tau mutation transcriptomics transdifferentiation

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.

项目摘要由tau引起的阿尔茨海默病(AD)和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。众所周知，多年来，tau并不是在大脑的所有细胞中积累，尽管tau在大脑中广泛表达 Tau基因。大脑的某些区域(以及其中的特定细胞群)特别容易受到堆积的病理形式的tau。原因尚不清楚，解决这一问题至关重要对于AD和FTD，以及其他表现出选择性易感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)特别容易受到牵张症的影响，并且，使用系统生物学方法，已确定缺乏tau稳态(蛋白稳态)是一个可能的机制。我们现在希望将这些研究扩展到一项关于衰老对兴奋状态下tau动态平衡通路的影响的研究与抑制性神经元相比，在人类和小鼠的大脑中，以及在一个新的人类衍生神经元模型中，测试其中一个途径(BAG3)是从转录组学中发现的。此外，我们将审查选择性的与FTD相关的原发神经元病患者的神经元易损性。最后，我们将使用RNA 艾伦研究所生成的数据集，用于识别兴奋性和抑制性之间的关键通路差异来自内嗅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稳定能力。这些研究将探索选择性易感性的基础，产生具有良好特征的资源，并有可能确定新的致病途径。