Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer’s Disease
| Autor: | Monika Pawlik, Seonil Kim, Chunfeng Huo, Shivakumar Subbanna, Philip Stavrides, Ju-Hyun Lee, Chris N. Goulbourne, Balapal S. Basavarajappa, Sandipkumar Darji, Ying Jiang, Cynthia Bleiwas, John F. Smiley, Ralph A. Nixon, James Peddy, Anna Pensalfini, Martin J. Berg |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Dendritic spine Endosomes AMPA receptor environment and public health Article General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences 0302 clinical medicine Alzheimer Disease Amyloid precursor protein Animals Humans Medicine Glycogen synthase rab5 GTP-Binding Proteins biology business.industry fungi Neurodegeneration Neurotoxicity Neurodegenerative Diseases medicine.disease Disease Models Animal enzymes and coenzymes (carbohydrates) 030104 developmental biology biology.protein Cholinergic biological phenomena cell phenomena and immunity business Amyloid precursor protein secretase Neuroscience 030217 neurology & neurosurgery |
| Zdroj: | Cell Rep |
| ISSN: | 2211-1247 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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