Neuronal C/EBPß/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression.

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.

C/EBPß is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer's disease.

The apolipoprotein E ε4 (APOE4) allele is a major genetic risk factor for Alzheimer's disease (AD), and its protein product, ApoE4, exerts its deleterious effects mainly by influencing amyloid-ß (Aß) and Tau (neurofibrillary tangles, NFTs) deposition in the brain. However, the molecular mechanism dictating its expression during ageing and in AD remains incompletely clear. Here we show that C/EBPß acts as a pivotal transcription factor for APOE and mediates its mRNA levels in an age-dependent manner. C/EBPß binds the promoter of APOE and escalates its expression in the brain. Knockout of C/EBPß in AD mouse models diminishes ApoE expression and Aß pathologies, whereas overexpression of C/EBPß accelerates AD pathologies, which can be attenuated by anti-ApoE monoclonal antibody or deletion of ApoE via its specific shRNA. Remarkably, C/EBPß selectively promotes more ApoE4 expression versus ApoE3 in human neurons, correlating with higher activation of C/EBPß in human AD brains with ApoE4/4 compared to ApoE3/3. Therefore, our data support that C/EBPß is a crucial transcription factor for temporally regulating APOE gene expression, modulating ApoE4's role in AD pathogenesis.