Neuronal C/EBPβ/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression
Yiyuan Xia, Hiroshi Qadota, Zhi-Hao Wang, Pai Liu, Xia Liu, Karen X. Ye, Courtney J. Matheny, Ken Berglund, Shan Ping Yu, Derek Drake, David A. Bennett, Xiaochuan Wang, Bruce A. Yankner, Guy M. Benian, Keqiang Ye
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/EBPβ, an Aβ 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/EBPβ transgenic mice. C/EBPβ 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/EBPβ 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/EBPβ/AEP pathway.