Endosomal Dysfunction Induced by Directly Over-Activating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer's Disease
| Autor: | Balapal S. Basavarajappa, Philip Stavrides, Chris N. Goulbourne, Monika Pawlik, Ju-Hyun Lee, Anna Pensalfini, Cynthia Bleiwas, Seonil Kim, Sandipkumar Darji, Martin J. Berg, Ying Jiang, John F. Smiley, Ralph A. Nixon, Shivakumar Subbanna, Chunfeng Huo |
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| Rok vydání: | 2019 |
| Předmět: |
Dendritic spine
fungi Neurodegeneration Neurotoxicity AMPA receptor Biology Hippocampal formation medicine.disease environment and public health enzymes and coenzymes (carbohydrates) medicine biology.protein Cholinergic biological phenomena cell phenomena and immunity Glycogen synthase Amyloid precursor protein secretase Neuroscience |
| Zdroj: | SSRN Electronic Journal. |
| ISSN: | 1556-5068 |
| Popis: | Neuronal endosomal dysfunction, the earliest known pathobiology specific to Alzheimer’s disease (AD), is mediated by aberrant activation of Rab5 triggered by APP-βeta secretase cleaved C-terminal fragment (APP-βCTF). To distinguish pathophysiological consequences specific to over-activated Rab5 itself, we activated Rab5 independently from APP-βCTF in a novel mouse model (PA-Rab5). We report that Rab5 over-activation alone recapitulates diverse prodromal and degenerative features of AD. Modest neuron-specific transgenic Rab5 expression inducing hyper-activation of Rab5 comparable to that in AD brain reproduced 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 induced progressive cholinergic neurodegeneration and impaired hippocampal dependent memory. Aberrant neuronal Rab5-endosome signaling, therefore, drives a novel pathogenic cascade distinct from β-amyloid-related neurotoxicity, which includes prodromal and neurodegenerative features of AD, and suggests Rab5 over-activation as a new therapeutic target. |
| Databáze: | OpenAIRE |
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