Endosome Dysfunction in Alzheimer's Disease

阿尔茨海默病中的内体功能障碍

• 批准号: 10219146
• 负责人: RALPH A. NIXON
• 金额: $ 72.66万
• 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/10219146
• 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阳性的内小体异常是一种标志性的病理。 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 为人所知。遗传数据已经独立地将内吞作用作为AD的主要早期靶点。我们有 研究表明，内小体异常的发生需要主蛋白Rab5的病理性过度激活。 调节早期内小体的GTP酶，触发显著上调的内吞作用和异常的内吞作用 融合、运输和细胞信号传递导致胆碱能神经变性。导致Rab5过度激活 AD和Down患者内体APP-B CTF(APP的B-裂解C-末端片段)水平升高 综合征(DS)，AD的原因之一，由于额外的应用程序副本。APP-BE CTF直接绑定和招募APPL1，a 信号效应器，它异常地稳定Rab5的激活(GTP加载)状态，触发内体 功能障碍。我们的新的表型强调了Rab5过度激活的致病重要性 阿尔茨海默病相关内小体功能障碍的神经元性Rab5过度激活转基因小鼠模型 以及在逆行转运、营养素信号、突触可塑性、认知和神经元存活方面的AD样缺陷， 所有这些都反映了Rb 5的损伤，S在神经元中扮演着许多已知的角色。我们认为早期内小体功能障碍 是启动晚发性阿尔茨海默病β-淀粉样蛋白形成的先期病理生物学的关键部分及其基础 基础，Rab5的超激活，进一步通过多条途径推动AD的发展。我们进一步建议 其他增加阿尔茨海默病风险的遗传影响，包括载脂蛋白E和GWAS确定的与内吞作用有关的基因 RAB5失调或加重RAB5对内体动力学和细胞的影响增加疾病风险 发信号。为了验证这些概念，我们将定义调控Rab5活性的多个途径/因素 神经元(Aim1a)和通过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循环和成熟(目标1b)。我们将定义 选择性激活Rab5对体内脑功能的影响并验证其预测的疾病- 阿尔茨海默病(AD)Happ(Wt)小鼠模型的加速效应(目标2)。令人兴奋的临床相关性，我们将在 在当前的临床试验中，AD治疗药物对内吞作用的预测作用，我们已经证明 在低纳摩尔浓度下逆转DS患者细胞中的Rab5激活和内小体功能障碍(目标3)。 我们将探讨APPL1和APPL2在直接将APP-？CTF与Rab5超激活联系起来的关键作用 在我们的小鼠中也证实了APPL1过表达或缺乏APPL1和/或APPL2，在这些小鼠中也是如此 与AD模型交叉(目标4)。我们将检验这样一种假设，即GWAAD风险基因与可疑的 内吞作用部分通过加剧由Rab5驱动的内小体功能障碍而增加风险(目标5)。这些都是新奇的 与AD的分子起源高度相关的AD病理生物学的未探索领域(S)。我们的终极 目标是识别和验证针对这种最早的AD病理生物学的创新疗法。