Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer's Disease.
Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer's Disease.
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DOI：
10.2139/ssrn.3512167
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发表时间：
2020-11
期刊：
影响因子：
8.8
通讯作者：
Anna Pensalfini;Seonil Kim;Shivakumar Subbanna;C. Bleiwas;C. Goulbourne;Philip H. Stavrides;Ying Jiang;Ju-Hyun Lee;Sandipkumar Darji;M. Pawlik;Chunfeng Huo;James Peddy;M. Berg;J. Smiley;B. Basavarajappa;R. Nixon
中科院分区：
文献类型：
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作者：
Anna Pensalfini;Seonil Kim;Shivakumar Subbanna;C. Bleiwas;C. Goulbourne;Philip H. Stavrides;Ying Jiang;Ju-Hyun Lee;Sandipkumar Darji;M. Pawlik;Chunfeng Huo;James Peddy;M. Berg;J. Smiley;B. Basavarajappa;R. Nixon
神经元内体功能障碍是阿尔茨海默病（Alzheimer's disease，AD）最早的病理学特征，由APP-β分泌酶切割的C端片段（APP-β secretase cleaved C-terminal fragment，APP-βCTF）引起Rab 5异常激活介导。为了区分过度激活Rab 5本身特有的病理生理学后果，我们在PA-Rab 5小鼠模型中独立于APP-βCTF激活Rab 5。我们报告说，Rab 5过度激活单独概括了不同的前驱和退行性特征的AD。适度的神经元特异性转基因Rab 5表达诱导Rab 5的过度激活，与AD脑中的表达相当，再现了AD相关的Rab 5内体扩大和误激活，通过加速的AMPAR内吞作用和树突棘损失的海马突触可塑性缺陷，以及通过激活的糖原合成酶激酶-3 β的tau过度磷酸化。重要的是，Rab 5介导的内体功能障碍诱导进行性胆碱能神经变性并损害海马依赖性记忆。因此，异常的神经元Rab 5-内体信号传导驱动不同于β-淀粉样蛋白相关神经毒性的致病性级联反应，其包括AD的前驱和神经退行性特征，并表明Rab 5过度活化作为潜在的治疗靶点。
Neuronal endosomal dysfunction, the earliest known pathobiology specific to Alzheimer's disease (AD), is mediated by the aberrant activation of Rab5 triggered by APP-β secretase cleaved C-terminal fragment (APP-βCTF). To distinguish pathophysiological consequences specific to overactivated Rab5 itself, we activate Rab5 independently from APP-βCTF in the PA-Rab5 mouse model. We report that Rab5 overactivation alone recapitulates diverse prodromal and degenerative features of AD. Modest neuron-specific transgenic Rab5 expression inducing hyperactivation of Rab5 comparable to that in AD brain reproduces AD-related Rab5-endosomal enlargement and mistrafficking, hippocampal synaptic plasticity deficits via accelerated AMPAR endocytosis and dendritic spine loss, and tau hyperphosphorylation via activated glycogen synthase kinase-3β. Importantly, Rab5-mediated endosomal dysfunction induces progressive cholinergic neurodegeneration and impairs hippocampal-dependent memory. Aberrant neuronal Rab5-endosome signaling, therefore, drives a pathogenic cascade distinct from β-amyloid-related neurotoxicity, which includes prodromal and neurodegenerative features of AD, and suggests Rab5 overactivation as a potential therapeutic target.