Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer’s Disease

• Published in: Cell reports (Cambridge) 2020-11, Vol.33 (8), p.108420-108420, Article 108420
• Main Authors: Pensalfini, Anna, Kim, Seonil, Subbanna, Shivakumar, Bleiwas, Cynthia, Goulbourne, Chris N., Stavrides, Philip H., Jiang, Ying, Lee, Ju-Hyun, Darji, Sandipkumar, Pawlik, Monika, Huo, Chunfeng, Peddy, James, Berg, Martin J., Smiley, John F., Basavarajappa, Balapal S., Nixon, Ralph A.
• Format: Article
• Language: English
• Subjects: aberrant endosomal signaling; Alzheimer Disease - genetics; Alzheimer Disease - physiopathology; Alzheimer’s disease; amyloid precursor protein; Animals; cholinergic neurodegeneration; Disease Models, Animal; endosomal dysfunction; Endosomes - metabolism; Humans; memory impairment; Mice; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - physiopathology; rab5 GTP-Binding Proteins - metabolism; Rab5 hyperactivation; spine loss; synaptic deficits; tau
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108420

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. [Display omitted] •Pathological Rab5 activation in PA-Rab5 mice mimics AD-like endosomal dysfunction•PA-Rab5 mice have synaptic function/structure deficits and GSK-3β-mediated tauopathy•Rab5 overactivation in vivo underlies cholinergic degeneration and memory deficits•Endosomal dysfunction alone induces prodromal and degenerative AD-related changes Pensalfini et al. generate mice reproducing neuron-specific pathological Rab5 activation (PA-Rab5) and elevated Rab5 expression as seen in AD, but independently of elevating APP-βCTF, its established trigger in AD. Rab5-mediated endosomal dysfunction drives a diverse prodromal/neurodegenerative cascade, independently of β-amyloid, suggesting that Rab5 may be a potential therapeutic target.