Casein Kinase 2 dependent phosphorylation of eIF4B regulates BACE1 expression in Alzheimer's disease.
Action Potentials
Alzheimer Disease
/ metabolism
Amyloid Precursor Protein Secretases
/ metabolism
Amyloid beta-Peptides
/ metabolism
Animals
Aspartic Acid Endopeptidases
/ metabolism
Casein Kinase II
/ antagonists & inhibitors
Disease Models, Animal
Eukaryotic Initiation Factors
/ metabolism
Gene Silencing
HEK293 Cells
Humans
Mice, Inbred C57BL
Neurons
/ drug effects
Phosphorylation
/ drug effects
Presenilin-1
/ metabolism
Protein Biosynthesis
/ drug effects
Protein Kinase Inhibitors
/ pharmacology
Up-Regulation
/ drug effects
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
04 08 2021
04 08 2021
Historique:
received:
19
03
2021
accepted:
12
07
2021
revised:
07
07
2021
entrez:
5
8
2021
pubmed:
6
8
2021
medline:
27
1
2022
Statut:
epublish
Résumé
Alzheimer's disease (AD) is the most common age-related neurodegenerative disorder. Increased Aβ production plays a fundamental role in the pathogenesis of the disease and BACE1, the protease that triggers the amyloidogenic processing of APP, is a key protein and a pharmacological target in AD. Changes in neuronal activity have been linked to BACE1 expression and Aβ generation, but the underlying mechanisms are still unclear. We provide clear evidence for the role of Casein Kinase 2 in the control of activity-driven BACE1 expression in cultured primary neurons, organotypic brain slices, and murine AD models. More specifically, we demonstrate that neuronal activity promotes Casein Kinase 2 dependent phosphorylation of the translation initiation factor eIF4B and this, in turn, controls BACE1 expression and APP processing. Finally, we show that eIF4B expression and phosphorylation are increased in the brain of APPPS1 and APP-KI mice, as well as in AD patients. Overall, we provide a definition of a mechanism linking brain activity with amyloid production and deposition, opening new perspectives from the therapeutic standpoint.
Identifiants
pubmed: 34349120
doi: 10.1038/s41419-021-04062-3
pii: 10.1038/s41419-021-04062-3
pmc: PMC8339060
doi:
Substances chimiques
Amyloid beta-Peptides
0
Eukaryotic Initiation Factors
0
Presenilin-1
0
Protein Kinase Inhibitors
0
eIF-4B
0
Casein Kinase II
EC 2.7.11.1
Amyloid Precursor Protein Secretases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
BACE1 protein, human
EC 3.4.23.46
Bace1 protein, mouse
EC 3.4.23.46
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
769Subventions
Organisme : European Molecular Biology Organization (EMBO)
ID : 7519
Organisme : Alzheimer Forschung Initiative (Alzheimer Forschung Initiative e.V.)
ID : 18014
Organisme : Regione Lombardia (Region of Lombardy)
ID : ID 239047
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca (Ministry of Education, University and Research)
ID : CTN01_00177_165430
Informations de copyright
© 2021. The Author(s).
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