Evidence for a clathrin-independent endocytic pathway for APP internalization in the neuronal somatodendritic compartment.
APP
Aβ
Bace1
CP: Cell biology
CP: Neuroscience
amyloid precursor protein
amyloid-beta
clathrin motif
dynamin
internalization
somatodendritic compartment
β-secretase
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
25 07 2023
25 07 2023
Historique:
received:
04
05
2022
revised:
08
05
2023
accepted:
25
06
2023
medline:
31
7
2023
pubmed:
14
7
2023
entrez:
14
7
2023
Statut:
ppublish
Résumé
Amyloid precursor protein (APP) internalization via clathrin-/dynamin-mediated endocytosis (CME) mediated by its YENPTY motif into endosomes containing β-secretase is proposed to be critical for amyloid-beta (Aβ) production. Here, we show that somatodendritic APP internalization in primary rodent neurons is not blocked by inhibiting dynamin or mutating the YENPTY motif, in contrast to non-neuronal cell lines. These phenomena, confirmed in induced human neurons under dynamin inhibition, occur during basal conditions and chemical long-term-depression stimulus, pointing to a clathrin-independent internalization pathway for somatodendritic APP. Mutating the YENPTY motif does not alter APP recycling, degradation, or endolysosomal colocalization. However, both dynamin inhibition and the YENPTY mutant significantly decrease secreted Aβ in neurons, suggesting that internalized somatodendritic APP may not constitute a major source of Aβ. Interestingly, like APP, somatodendritic low-density lipoprotein receptor (LDLR) internalization does not require its CME motif. These results highlight intriguing differences in neuronal internalization pathways and refine our understanding of Aβ production and secretion.
Identifiants
pubmed: 37450368
pii: S2211-1247(23)00785-4
doi: 10.1016/j.celrep.2023.112774
pmc: PMC10449584
mid: NIHMS1920506
pii:
doi:
Substances chimiques
Amyloid beta-Protein Precursor
0
Clathrin
0
Amyloid beta-Peptides
0
Amyloid Precursor Protein Secretases
EC 3.4.-
Dynamins
EC 3.6.5.5
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
112774Subventions
Organisme : NINDS NIH HHS
ID : R01 NS084324
Pays : United States
Informations de copyright
Copyright © 2023 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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