Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.
Neuroscience program, Laney Graduate School, Emory University, Atlanta, GA 30322, USA.
Sci Adv. 2022 Apr;8(13):eabj8658. doi: 10.1126/sciadv.abj8658. Epub 2022 Mar 30.
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 neurons but not muscle stimulates neural excitation and shortens life span. CEBP-2 or LGMN-1 reduces mutant-elongated life span and diminishes -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.
正常衰老引起的认知能力下降在神经退行性疾病中更为严重，包括阿尔茨海默病（AD）。然而，AD 病理中的与年龄相关的认知调节因子是否会影响寿命仍不清楚。在这里，我们表明，C/EBPβ 是一种 Aβ 和炎症细胞因子激活的转录因子，通过激活天冬酰胺内肽酶（AEP）促进 AD 病理，以神经元 C/EBPβ 转基因小鼠中基因剂量依赖的方式介导长寿。C/EBPβ 通过抑制 FOXO 和上调 AEP 选择性地触发抑制性 GABA 能神经元变性，导致异常的神经兴奋和认知功能障碍。神经元中 CEBP-2 或 LGMN-1（AEP）的过表达而不是肌肉刺激神经兴奋并缩短寿命。CEBP-2 或 LGMN-1 减少了突变体的延长寿命并降低了诱导的长寿。具有延长寿命的人类中 C/EBPβ 和 AEP 水平较低，与 REST/FOXO1 呈负相关。这些发现表明，衰老的保守机制通过神经元 C/EBPβ/AEP 途径将病理性认知下降与寿命联系起来。
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