Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer's Disease.
Alzheimer’s disease
Rab5 hyperactivation
aberrant endosomal signaling
amyloid precursor protein
cholinergic neurodegeneration
endosomal dysfunction
memory impairment
spine loss
synaptic deficits
tau
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
24 11 2020
24 11 2020
Historique:
received:
17
12
2019
revised:
05
06
2020
accepted:
02
11
2020
entrez:
25
11
2020
pubmed:
26
11
2020
medline:
17
12
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 33238112
pii: S2211-1247(20)31409-1
doi: 10.1016/j.celrep.2020.108420
pmc: PMC7714675
mid: NIHMS1649681
pii:
doi:
Substances chimiques
rab5 GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
108420Subventions
Organisme : NIA NIH HHS
ID : P01 AG017617
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG062376
Pays : United States
Informations de copyright
Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The authors declare no competing interests.
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