Mechanisms of amyloid-β34 generation indicate a pivotal role for BACE1 in amyloid homeostasis.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
07 02 2023
07 02 2023
Historique:
received:
10
11
2022
accepted:
25
01
2023
entrez:
7
2
2023
pubmed:
8
2
2023
medline:
10
2
2023
Statut:
epublish
Résumé
The beta‑site amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its "amyloidogenic" activity which contributes to the production of amyloid-beta (Aβ) peptides. However, BACE1 also possesses an "amyloidolytic" activity, whereby it degrades longer Aβ peptides into a non‑toxic Aβ34 intermediate. Here, we examine conditions that shift the equilibrium between BACE1 amyloidogenic and amyloidolytic activities by altering BACE1/APP ratios. In Alzheimer disease brain tissue, we found an association between elevated levels of BACE1 and Aβ34. In mice, the deletion of one BACE1 gene copy reduced BACE1 amyloidolytic activity by ~ 50%. In cells, a stepwise increase of BACE1 but not APP expression promoted amyloidolytic cleavage resulting in dose-dependently increased Aβ34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in Aβ34 levels. To align the role of γ-secretase in this pathway, we silenced Presenilin (PS) expression and identified PS2-γ-secretase as the main γ-secretase that generates Aβ40 and Aβ42 peptides serving as substrates for BACE1's amyloidolytic cleavage to generate Aβ34.
Identifiants
pubmed: 36750595
doi: 10.1038/s41598-023-28846-z
pii: 10.1038/s41598-023-28846-z
pmc: PMC9905473
doi:
Substances chimiques
Amyloid Precursor Protein Secretases
EC 3.4.-
Aspartic Acid Endopeptidases
EC 3.4.23.-
Amyloid beta-Protein Precursor
0
Amyloid beta-Peptides
0
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
2216Subventions
Organisme : CIHR
ID : PJT-173407
Pays : Canada
Organisme : CIHR
ID : MOP-133411
Pays : Canada
Informations de copyright
© 2023. The Author(s).
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