Targeted BACE-1 inhibition in microglia enhances amyloid clearance and improved cognitive performance.
Sci Adv
; 8(29): eabo3610, 2022 07 22.
Article
en En
| MEDLINE
| ID: mdl-35857844
ABSTRACT
Abnormal accumulation of ß-amyloid (Aß) peptides is a culprit in Alzheimer's disease (AD); blocking Aß generation is therefore being explored as a logical approach for AD treatment. Here, we demonstrate that targeted inhibition of ß-site amyloid precursor protein (APP) cleaving enzyme-1 (BACE-1) in microglia has unique advantages. When Bace-1 was deleted in Alzheimer's 5xFAD microglia, fewer amyloid plaques developed, and this reduction was not due to changes in APP processing but rather to enhanced Aß clearance, in line with the increase in a microglial gene signature favoring phagocytosis. Moreover, deletion of Bace-1 in microglia enhances functions of autophagolysosomes and Aß-induced metabolic reprogramming necessary for Aß degradation by favoring phosphorylation of mammalian target of rapamycin complex (mTOR) at Ser2448 and modulating the PI3K-mTOR-HIF-1α signaling pathways. Mice with deletion of Bace-1 in microglia showed no reduction in long-term potentiation, unlike global deletion of Bace-1. Our results suggest that targeted inhibition of BACE-1 in microglia is a superior strategy for AD treatment.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Ácido Aspártico Endopeptidasas
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Microglía
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Secretasas de la Proteína Precursora del Amiloide
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Enfermedad de Alzheimer
Límite:
Animals
Idioma:
En
Revista:
Sci Adv
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos