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Endosome Dysfunction in Alzheimer's Disease

阿尔茨海默病中的内体功能障碍

基本信息

批准号：
9977870
负责人：
RALPH A. NIXON
金额：
$ 74.12万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977870
关键词：
Acceleration Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Amyloid beta-Protein Precursor Apolipoprotein E Area Binding Biological Brain C-terminal Cell model Cells Cholesterol Cleaved cell Clinical Trials Cognition Data Development Disease Down Syndrome Early Endosome Endocytosis Endosomes Event Frequencies Functional disorder Genes Genetic Genetic Transcription Guanosine Triphosphate Guanosine Triphosphate Phosphohydrolases Health Impaired cognition Impairment In Vitro Knowledge Late Onset Alzheimer Disease Ligands Link MAP Kinase Gene Metabolism Modeling Molecular Monomeric GTP-Binding Proteins Mus Mutation Nerve Degeneration Neurons Other Genetics Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Phenotype Proteins Recycling Regulation Reporting Research Risk Role Route Signal Transduction Signaling Protein Structure Synapses Synaptic plasticity Synaptosomes Testing Therapeutic Transgenic Mice Transgenic Organisms Up-Regulation abeta deposition amyloid precursor protein processing amyloidogenesis brain cell cholinergic clinically relevant disorder risk genome wide association study in vivo in vivo Model innovation lipid transport mouse model nanomolar neuropathology novel overexpression p38 Mitogen Activated Protein Kinase recruit retrograde transport risk variant therapeutic target trafficking

项目摘要

Two decades ago, we identified abnormalities of rab5-positive endosomes as a signature pathology of Alzheimer’s disease (AD), which is considered the earliest appearing neuronal pathology specific to AD yet known. Genetic data have independently converged on endocytosis as a prime early target in AD. We have shown that development of endosome anomalies requires pathological hyper-activation of rab5, the master regulatory GTPase on early endosomes, to trigger markedly upregulated endocytosis and aberrant endosomal fusion, trafficking, and cell signaling leading to cholinergic neurodegeneration. Rab5 over-activation is caused by elevated endosomal levels of APP-ßCTF (ß-cleaved C-terminal fragment of APP) in AD and in Down Syndrome (DS), a cause of AD due to an extra APP copy. APP-ßCTF directly binds and recruits APPL1, a signaling effector, which aberrantly stabilizes the activated (GTP-loaded) state of rab5, triggering endosomal dysfunction. The pathogenic importance of rab5 over-activation is underscored by the phenotype of our new transgenic mouse model of neuronal rab5 over-activation, which develops AD-related endosome dysfunction and AD-like deficits in retrograde transport, trophin signaling, synaptic plasticity, cognition, and neuron survival, all reflecting impairment of rab5’s many known roles in neurons. We propose that early endosome dysfunction is a key part of the antecedent pathobiology initiating ß-amyloidogenesis in late-onset AD and that its underlying basis, rab5 hyper-activation, further drives AD development through multiple pathways. We further propose that other genetic influences increasing AD risk, including ApoE and GWAS-identified genes with roles in endocytosis increase disease risk by dysregulating rab5 or exacerbating rab5’s impact on endosome dynamics and cell signaling. To validate these concepts, we will define the multiple pathways/factors that regulate rab5 activity in neurons (Aim1a) and that initiate AD-related endosome dysfunction via rab5 and additional factors controlling endosomal recycling and maturation in cell and mouse models of AD and DS (Aim 1b). We will define the consequences of selective rab5 over-activation on brain function in vivo and validate its predicted disease- accelerating effects in an hAPP(wt) mouse model of AD(Aim 2). Of exciting clinical relevance, we will validate in vivo the predicted actions on endocytosis of an AD therapeutic in current clinical trials, which we have shown to reverse rab5 activation and endosome dysfunction in DS patient cells at low nanomolar concentrations (Aim 3). The crucial roles of APPL1 and APPL2 in directly linking APP- ßCTF to rab5 hyper-activation will be explored and also validated in our mice that over-express APPL1 or lack APPL1 and/or APPL2 and also in these mice crossed to AD models (Aim 4). We will test the hypothesis that GWAS AD risk genes with suspected roles in endocytosis confer risk in part by exacerbating rab5-driven endosome dysfunction (Aim 5). These are all novel unexplored areas of AD pathobiology that are highly relevant to the molecular origin(s) of AD. Our ultimate objectives are identifying and validating innovative therapeutics that target this earliest AD pathobiology.

二十年前，我们发现rab5阳性核内体异常是乳腺癌的一种特征病理