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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：
10221595
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10221595
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 Dose Encephalitis Event Frontotemporal Dementia Functional disorder GRN gene Gene Expression Genes Genetic Genetic Variation Genetic study Glycoproteins Goals Hippocampus (Brain)Human Human Genetics Impairment In Vitro Individual Inflammatory Knowledge Late Onset Alzheimer Disease Link 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 Risk Role Senile Plaques Sorting - Cell Movement System Tauopathies Testing Toxic effect Transgenes Transgenic Model Transgenic Organisms Up-Regulation Variant Work abeta accumulation behavioral study cohort experimental study gene product glucosylceramidase in vivo inhibitor/antagonist neuropathology prion-like protein TDP-43 receptor risk variant sortilin spatial memory tau Proteins tau aggregation tau expression tau interaction tau mutation tau phosphorylation

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.

总结阿尔茨海默病（AD）进展缓慢，涉及许多分子途径。除了积累在AAF斑块和Tau神经元缠结中，也存在炎症、血管和代谢变化。晚发性AD（LOAD）风险的人类遗传学研究已经确定了两组主要基因，一组与脑炎症和另一种在内溶酶体途径中具有确定作用。内溶酶体细胞器被细胞用来吸收、降解和去除细胞内外的物质。的 AD中内溶酶体调节/失调的一般原理还不清楚。但安在退行性痴呆中，内溶酶体途径的作用不是AD所特有的。在相关条件下，额颞叶痴呆，颗粒蛋白前体和TMEM106 B蛋白发挥关键作用，并与内溶酶体途径在这里，我们试图利用这一FTLD-TDP途径的知识来理解和改变AD和Tau病中的内溶酶体功能。我们对缺乏颗粒蛋白前体的小鼠的研究表明，这种内溶酶体蛋白对 Tau依赖性神经变性在初步研究中，Tau转基因诱导的表型被完全拯救，失去了颗粒蛋白原在拟议的工作中，我们将描述这一令人兴奋的发现与分子以及Tau聚集、磷酸化、扩散、代谢和毒性的细胞细节。这些研究将定义了Tau病（包括AD）中内溶酶体的前粒蛋白依赖性调节的作用。失去第二种内溶酶体蛋白TMEM106 B在某些情况下抵消颗粒蛋白原的损失，但在其他情况下不起作用。对于Tau病和AD，我们将测试TMEM106 B功能的降低是否与病理生理学相关，以及是否与TMEM106 B功能的降低相关。增加TMEM 106 B模拟颗粒蛋白前体的损失以挽救Tau病。长期目标是确定一个神经变性相关的内溶酶体途径，可靶向提供疾病缓解治疗包括老年痴呆症在内的Tau病