Endosome Dysfunction in Alzheimer's Disease

阿尔茨海默病中的内体功能障碍

• 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
• 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' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer' 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

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 阳性内体异常是 阿尔茨海默病 (AD)，被认为是迄今为止最早出现的 AD 特有的神经元病理学 已知。遗传数据独立地认为内吞作用是 AD 的主要早期目标。我们有 表明内体异常的发展需要 rab5（主宰者）的病理性过度激活 早期内体上的调节性 GTP 酶，引发显着上调的内吞作用和异常的内体 融合、运输和细胞信号传导导致胆碱能神经变性。 Rab5过度激活所致 AD 和 Down 中 APP-ßCTF（APP 的 ß-切割 C 端片段）内体水平升高 综合症 (DS)，由于额外的 APP 副本而导致 AD 的原因。 APP-ßCTF 直接结合并招募 APPL1， 信号传导效应器，异常稳定 rab5 的激活（GTP 负载）状态，触发内体 功能障碍。我们的新表型强调了 rab5 过度激活的致病重要性 神经元 rab5 过度激活的转基因小鼠模型，导致 AD 相关内体功能障碍 以及逆行运输、肌营养蛋白信号传导、突触可塑性、认知和神经元存活方面的 AD 样缺陷， 所有这些都反映出 rab5 在神经元中许多已知作用的损害。我们认为早期内体功能障碍 是迟发性 AD 中启动 β-淀粉样蛋白生成的先行病理学的关键部分，其根本原因是 在此基础上，rab5 的过度激活通过多种途径进一步驱动 AD 的发展。我们进一步建议 其他增加 AD 风险的遗传影响，包括 ApoE 和 GWAS 鉴定的在内吞作用中起作用的基因 通过 rab5 失调或加剧 rab5 对内体动力学和细胞的影响来增加疾病风险 发信号。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 和其他控制因子启动 AD 相关内体功能障碍 AD 和 DS 细胞和小鼠模型中的内体回收和成熟（目标 1b）。我们将定义 选择性 rab5 过度激活对体内脑功能的影响并验证其预测的疾病- AD 的 hAPP(wt) 小鼠模型中的加速效应（目标 2）。具有令人兴奋的临床相关性，我们将在 在当前的临床试验中，我们已经证明了 AD 治疗药物对内吞作用的预测作用 在低纳摩尔浓度下逆转 DS 患者细胞中的 rab5 激活和内体功能障碍（目标 3）。 将探讨 APPL1 和 APPL2 在直接将 APP-ßCTF 与 rab5 过度激活联系起来方面的关键作用 并且还在我们过度表达 APPL1 或缺乏 APPL1 和/或 APPL2 的小鼠以及这些小鼠中进行了验证 交叉到 AD 模型（目标 4）。我们将检验以下假设：GWAS AD 风险基因在 内吞作用部分通过加剧 rab5 驱动的内体功能障碍而带来风险（目标 5）。这些都很新颖 AD 病理学中与 AD 分子起源高度相关的未探索领域。我们的终极 目标是识别和验证针对这一最早的 AD 病理学的创新疗法。