Rheb GTPase regulates ß-secretase levels and amyloid ß generation.
J Biol Chem
; 289(9): 5799-808, 2014 Feb 28.
Article
em En
| MEDLINE
| ID: mdl-24368770
ABSTRACT
The ß-site amyloid precursor protein (APP)-cleaving enzyme 1 (ß-secretase, BACE1) initiates amyloidogenic processing of APP to generate amyloid ß (Aß), which is a hallmark of Alzheimer disease (AD) pathology. Cerebral levels of BACE1 are elevated in individuals with AD, but the molecular mechanisms are not completely understood. We demonstrate that Rheb GTPase (Ras homolog enriched in brain), which induces mammalian target of rapamycin (mTOR) activity, is a physiological regulator of BACE1 stability and activity. Rheb overexpression depletes BACE1 protein levels and reduces Aß generation, whereas the RNAi knockdown of endogenous Rheb promotes BACE1 accumulation, and this effect by Rheb is independent of its mTOR signaling. Moreover, GTP-bound Rheb interacts with BACE1 and degrades it through proteasomal and lysosomal pathways. Finally, we demonstrate that Rheb levels are down-regulated in the AD brain, which is consistent with an increased BACE1 expression. Altogether, our study defines Rheb as a novel physiological regulator of BACE1 levels and Aß generation, and the Rheb-BACE1 circuitry may have a role in brain biology and disease.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Neuropeptídeos
/
Encéfalo
/
Ácido Aspártico Endopeptidases
/
Precursor de Proteína beta-Amiloide
/
Proteínas Monoméricas de Ligação ao GTP
/
Secretases da Proteína Precursora do Amiloide
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article