Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals.
APP knockin mice
Alzheimer's disease
amyloid beta
mass spectrometry
presynapse
proteomics
proteostasis
synaptic dysfunction
synaptic vesicles
Journal
Cell systems
ISSN: 2405-4720
Titre abrégé: Cell Syst
Pays: United States
ID NLM: 101656080
Informations de publication
Date de publication:
17 02 2021
17 02 2021
Historique:
received:
21
04
2020
revised:
23
09
2020
accepted:
19
11
2020
pubmed:
17
12
2020
medline:
15
12
2021
entrez:
16
12
2020
Statut:
ppublish
Résumé
Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer's disease (AD). To observe protein turnover at early stages of amyloid beta (Aβ) proteotoxicity, we performed pulse-chase proteomics on mouse brains in three genetic models of AD that knock in alleles of amyloid precursor protein (APP) prior to the accumulation of plaques and during disease progression. At initial stages of Aβ accumulation, the turnover of proteins associated with presynaptic terminals is selectively impaired. Presynaptic proteins with impaired turnover, particularly synaptic vesicle (SV)-associated proteins, have elevated levels, misfold in both a plaque-dependent and -independent manner, and interact with APP and Aβ. Concurrent with elevated levels of SV-associated proteins, we found an enlargement of the SV pool as well as enhancement of presynaptic potentiation. Together, our findings reveal that the presynaptic terminal is particularly vulnerable and represents a critical site for manifestation of initial AD etiology. A record of this paper's transparent peer review process is included in the Supplemental Information.
Identifiants
pubmed: 33326751
pii: S2405-4712(20)30458-0
doi: 10.1016/j.cels.2020.11.007
pmc: PMC7897324
mid: NIHMS1661508
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
141-158.e9Subventions
Organisme : NIA NIH HHS
ID : F31 AG059364
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG061865
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS107761
Pays : United States
Organisme : NIA NIH HHS
ID : T32 AG020506
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA060553
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG061787
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH099114
Pays : United States
Organisme : NIA NIH HHS
ID : RF1 AG061829
Pays : United States
Organisme : NIMH NIH HHS
ID : R01 MH061876
Pays : United States
Organisme : Howard Hughes Medical Institute
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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