阿尔茨海默病和 FTLD-TDP 中内溶酶体功能的重叠分子失调-猫眼课题宝

阿尔茨海默病和 FTLD-TDP 中内溶酶体功能的重叠分子失调

批准号：

10642722

负责人：

STEPHEN M STRITTMATTER

金额：

$77.53万

依托单位：

YALE UNIVERSITY

依托单位国家：

美国

项目类别：

财政年份：

2019

资助国家：

美国

项目状态：

未结题

起止时间：

2019-09-15 至 2025-05-31

来源：

https://reporter.nih.gov/project-details/10642722

关键词：

ATP binding cassette transporter 1 ATP6AP1 gene Acute Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease risk Alzheimer&apos s disease therapy Alzheimer’s disease biomarker Amyloid beta-Protein Astrocytes Autophagocytosis Binding Sites Blood Vessels Brain CLN1 gene Cell surface Cells Cerebral cortex Chronic Data Dementia Development Disease Disease Progression Dose Encephalitis Event Frontotemporal Dementia Frontotemporal Lobar Degenerations Functional disorder GRN gene Gene Expression Genes Genetic Genetic Variation Genetic study Glycoproteins Goals Hippocampus Human Human Genetics Impairment In Vitro Individual Inflammatory Knowledge Late Onset Alzheimer Disease Link Lysosomal Storage Diseases Lysosomes Medical Memory Loss Metabolic Metabolism Microglia Modeling Molecular Mus Nerve Degeneration Neuronal Ceroid-Lipofuscinosis Neurons Organelles PGRN gene Pathology Pathway interactions Peptide Hydrolases Phenotype Phosphorylation Play Proteins Publishing Reaction Regulation Retina Role Senile Plaques Sorting System Tauopathies Testing Titrations Toxic effect Transgenes Transgenic Model Transgenic Organisms Up-Regulation Variant Work abeta accumulation behavioral study cohort experimental study gene product glucosylceramidase in vivo inhibitor neuropathology prion-like protein TDP-43 receptor risk variant sortilin spatial memory tau Proteins tau aggregation tau expression tau interaction tau mutation tau-1

中文摘要

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英文摘要

SUMMARY Alzheimer’s Disease (AD) progresses slowly and involves many molecular pathways. In addition to accumulation of Aß plaques and Tau neurofibrillary tangles, there are also inflammatory, vascular and metabolic changes. Human genetic studies of late onset AD (LOAD) risk have identified two major groups of genes, one related to brain inflammation and another with established roles in the endolysosomal pathway. Endolysosomal organelles are utilized by cells to take up, degrade and remove substances from both inside and outside of the cell. The general principles of endolysosomal regulation/dysregulation in AD are not well understood. However, an endolysosomal pathway role is not specific to AD amongst degenerative dementias. In the related condition of Fronto-Temporal Dementia, Progranulin and TMEM106B proteins play key roles, and are linked to the endolysosomal pathway. Here, we seek to leverage knowledge of this FTLD-TDP pathway to understand and modify endolysosomal function in AD and in Tauopathy. Our studies of mice lacking Progranulin suggest that this endolysosomal protein has a pronounced effect on Tau-dependent neuro-degeneration. In Preliminary studies, Tau transgene induced phenotypes are fully rescued by loss of Progranulin. In proposed work, we will characterize this exciting finding with regard to the molecular and cellular details of Tau aggregation, phosphorylation, spreading, metabolism and toxicity. These studies will define a role of Progranulin-dependent regulation of endolysosomes in Tauopathies, including AD. Loss of a second endolysosomal protein, TMEM106B, counteracts loss of Progranulin in certain settings, but not others. For Tauopathy and AD, we will test whether reducing TMEM106B function worsens pathophysiology, and if increasing TMEM106B mimics the loss of Progranulin to rescue Tauopathy. The long-term goal is to define a neuro-degeneration-related endolysosomal pathway that can be targeted to provide disease-modifying therapy for Tauopathies, including Alzheimer’s Disease.

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