Neuronal C/EBPß/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression.
Sci Adv
; 8(13): eabj8658, 2022 04.
Article
em En
| MEDLINE
| ID: mdl-35353567
ABSTRACT
The age-related cognitive decline of normal aging is exacerbated in neurodegenerative diseases including Alzheimer's disease (AD). However, it remains unclear whether age-related cognitive regulators in AD pathologies contribute to life span. Here, we show that C/EBPß, an Aß and inflammatory cytokine-activated transcription factor that promotes AD pathologies via activating asparagine endopeptidase (AEP), mediates longevity in a gene dose-dependent manner in neuronal C/EBPß transgenic mice. C/EBPß selectively triggers inhibitory GABAnergic neuronal degeneration by repressing FOXOs and up-regulating AEP, leading to aberrant neural excitation and cognitive dysfunction. Overexpression of CEBP-2 or LGMN-1 (AEP) in Caenorhabditis elegans neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces daf-2 mutant-elongated life span and diminishes daf-16-induced longevity. C/EBPß and AEP are lower in humans with extended longevity and inversely correlated with REST/FOXO1. These findings demonstrate a conserved mechanism of aging that couples pathological cognitive decline to life span by the neuronal C/EBPß/AEP pathway.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas de Caenorhabditis elegans
/
Longevidade
Limite:
Animals
Idioma:
En
Revista:
Sci Adv
Ano de publicação:
2022
Tipo de documento:
Article
País de afiliação:
Estados Unidos