Apolipoprotein E4 inhibits γ-secretase activity via binding to the γ-secretase complex.
J Neurochem
; 164(6): 858-874, 2023 03.
Article
em En
| MEDLINE
| ID: mdl-36582176
ABSTRACT
The mechanisms of amyloid accumulation in familial Alzheimer's disease (FAD) and sporadic AD (SAD) are controversial. In FAD, mutations in presenilin (PSEN) impair γ-secretase activity and lead to abnormal amyloid ß-protein (Aß) production, thereby increasing the Aß42/40 ratio. SAD is postulated to be caused by decreased Aß clearance of apolipoprotein E4 (APOE4), the strongest risk factor for SAD. However, whether intracellular APOE4 affects Aß production is unclear. Using APOE3 and APOE4 knock-in (KI) mouse brain and primary cultured fibroblasts from these mice, in this study, we demonstrated that APOE3 and APOE4 bind to the γ-secretase complex and isoform-dependently regulate its activity and Aß production. We found that Aß40 levels and γ-secretase activity were higher in APOE knockout mouse brain than in wild-type mouse brain. APOE4-KI fibroblasts had significant lower Aß levels and γ-secretase activity but higher Aß42/40 ratio compared with APOE3-KI cells, indicating that APOE4-KI reduces Aß production by inhibiting γ-secretase activity. Interestingly, the levels of γ-secretase complex bound to APOE4 are higher than those bound to APOE3, and the levels of γ-secretase complex in the brain and fibroblasts of APOE4-KI mice were higher than those of APOE3-KI mice. Taken together, our findings demonstrate that intracellular APOE4 inhibits Aß production, more preferentially inhibits Aß40 production, and thereby induces an increase in the Aß42/40 ratio via binding to the γ-secretase complex. These results suggest a novel mechanism in which intracellular APOE4 contributes to the pathogenesis of SAD by inhibiting γ-secretase activity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Apolipoproteína E4
/
Doença de Alzheimer
Limite:
Animals
Idioma:
En
Revista:
J Neurochem
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Japão