Overlapping Molecular Dysregulation of Endolysosomal Function in Alzheimer's Disease and FTLD-TDP

阿尔茨海默病和 FTLD-TDP 中内溶酶体功能的重叠分子失调

基本信息

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
起止时间：
2019-09-15 至 2025-05-31
项目状态：
未结题

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

项目摘要

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.

概括阿尔茨海默氏病（AD）进展缓慢，涉及许多分子途径。除了积累 Aß斑块和tau神经原纤维缠结的缠结，也有炎症，血管和代谢变化。晚期AD（负载）风险的人类遗传研究已经确定了两个主要基因，一个与脑感染，另一个在内溶液途径中具有确定的作用。内溶血细胞器通过细胞利用来吸收，降解和去除细胞内外的物质。 AD中内溶性调节/失调的一般原理尚不清楚。但是，一个内溶性途径的角色不是退化性痴呆中的AD特定的。在相关条件下额新的痴呆症，progranulin和TMEM106B蛋白扮演关键角色，并与内侧溶血途径。在这里，我们试图利用这种FTLD-TDP途径的知识来理解和在AD和Tauopathy中修改内溶性函数。我们对缺乏尿素蛋白的小鼠的研究表明，这种内溶性蛋白具有明显的影响 tau依赖性神经脱生。在初步研究中，tau变换诱导的表型已完全恢复通过失去前植物。在拟议的工作中，我们将描述有关分子的令人兴奋的发现以及tau聚集，磷酸化，扩散，代谢和毒性的细胞细节。这些研究会定义了包括AD在内的aupathies中内溶性的依赖性蛋白依赖性调节的作用。损失第二个内溶性蛋白TMEM106B可以抵消某些情况下的疾病损失，而不是其他情况。对于Tauopathy和AD，我们将测试降低TMEM106B功能是否会使病理生理恶化，以及是否存在增加TMEM106B模仿了促进tauopathy的前植物丧失。长期目标是定义神经脱生相关的内溶性途径，该途径可用于提供疾病改良疗法对于包括阿尔茨海默氏病在内的陶氏病。