Mechanisms of amyloid-ß34 generation indicate a pivotal role for BACE1 in amyloid homeostasis.
Sci Rep
; 13(1): 2216, 2023 02 07.
Article
em En
| MEDLINE
| ID: mdl-36750595
ABSTRACT
The betasite amyloid precursor protein (APP) cleaving enzyme (BACE1) was discovered due to its "amyloidogenic" activity which contributes to the production of amyloid-beta (Aß) peptides. However, BACE1 also possesses an "amyloidolytic" activity, whereby it degrades longer Aß peptides into a nontoxic Aß34 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 Aß34. 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 Aß34 levels. At the cellular level, a mislocalization of surplus BACE1 caused a reduction in Aß34 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 Aß40 and Aß42 peptides serving as substrates for BACE1's amyloidolytic cleavage to generate Aß34.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Secretases da Proteína Precursora do Amiloide
/
Doença de Alzheimer
Limite:
Animals
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Canadá