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.

项目摘要阿尔茨海默氏病（AD）和额叶叶变性谱系疾病由Tau引起（FTD-TAU）是两个神经退行性疾病，这些疾病以异常tau的累积为特征。多年以来，尽管tau在大脑的所有细胞中都没有积累 tau基因。累积tau的病理形式。对于AD和FTD，以及我们观察到的其他神经退行性疾病那个表现神经元（与inbiberneurons相比）特别容易受到tauopathy的影响，并使用系统生物学方法已确定tau稳态（蛋白质稳定）是一种可能的机制现在希望将研究扩展到有关衰老对兴奋性tau稳态途径的影响的研究与吸入性神经元，人和小鼠脑以及新型的人类衍生的神经元模型相比，测试另一个途径（BAG3）与转录组有关。与FTD相关的原发性分妥妥杆菌患者神经元的脆弱性。艾伦学院（Allen Institute 来自肠道皮质的神经元开始识别和抑制细胞的神经元在其上可能有所不同这些研究的能力将探索选择性脆弱性的基础特征良好的资源，并有可能识别导致途径的新疾病。