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：
10433977
负责人：
RALPH A. NIXON
金额：
$ 71.15万
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 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10433977
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 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，我们将Rab5阳性内体的异常确定为一种签名病理学阿尔茨海默氏病（AD），被认为是最早的AD神经元病理学已知。遗传数据已在内吞作用上独立融合，作为AD的主要早期靶标。我们有表明内体异常的发展需要RAB5的病理过度激活，早期内体的监管GTPase，以触发明显更新的内吞和异常内体融合，运输和细胞信号传导导致胆碱能神经退行性。 Rab5过度激活是引起的通过AD和Down中的App-ßctf（APP的C末端片段）的内体水平升高综合征（DS），由于额外的应用程序副本而引起的广告原因。 app-ßctf直接绑定和招募appl1，a 信号效应器异常稳定了RAB5的活化（GTP负载）状态，从而触发内体功能障碍。 Rab5过度激活的致病意义被我们的新表型强调了神经元Rab5过度激活的转基因小鼠模型，该模型会出现与AD相关的内体功能障碍广告状定义在逆行运输，Trophin信号传导，突触可塑性，认知和神经元存活中的定义，所有这些都反映了Rab5在神经元中许多已知角色的损害。我们建议早期内体功能障碍是前期病理生物学的关键部分，在晚期AD中β-淀粉样蛋白发生基础，RAB5过度激活，进一步通过多种途径驱动AD开发。我们进一步提出了其他遗传影响增加了AD风险，包括APOE和GWAS鉴定的基因，在内吞作用中作用通过失调RAB5或加剧RAB5对内体动力学和细胞的影响来增加疾病的风险信号。为了验证这些概念，我们将定义调节Rab5活性的多种途径/因素神经元（AIM1A）并通过RAB5启动与广告相关的内体功能障碍以及控制的其他因素 AD和DS的细胞和小鼠模型中的内体回收和成熟（AIM 1B）。我们将定义选择性rab5过度激活对体内脑功能的后果，并验证其预测的疾病 - 在AD的HAPP（WT）鼠标模型中加速效应（AIM 2）。令人兴奋的临床相关性，我们将验证体内在当前临床试验中对AD疗法内吞作用的预测作用，我们已证明这是在低纳摩尔浓度下，DS患者细胞中的RAB5激活和内体功能障碍（AIM 3）。将探索Appl1和Appl2在直接链接app-ctf与Rab5高激活中的关键作用并且在我们的小鼠中也证实了过表达Appl1或缺乏Appl1和/或Appl2以及这些小鼠越过广告模型（AIM 4）。我们将检验以下假设：GWAS AD风险基因在内吞作用会议会议风险部分通过加剧RAB5驱动的内体功能障碍（AIM 5）。这些都是新颖的与AD分子起源高度相关的AD病理生物学领域。我们的最终目标正在识别和验证针对这种最早的AD病理生物学的创新治疗剂。