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神经元 C/EBPβ/AEP 通路通过 FOXO 抑制选择性 GABA 能神经元变性缩短寿命。

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

机构信息

Department of Pathology and Laboratory Medicine, Emory University, Atlanta, GA 30322, USA.

Neuroscience program, Laney Graduate School, Emory University, Atlanta, GA 30322, USA.

出版信息

Sci Adv. 2022 Apr;8(13):eabj8658. doi: 10.1126/sciadv.abj8658. Epub 2022 Mar 30.

DOI:10.1126/sciadv.abj8658
PMID:35353567
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8967231/
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 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.

摘要

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。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/92538b54994c/sciadv.abj8658-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/35ce2bbadf60/sciadv.abj8658-f1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/74c9fcc8fbf2/sciadv.abj8658-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/bc320babb124/sciadv.abj8658-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/92538b54994c/sciadv.abj8658-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/35ce2bbadf60/sciadv.abj8658-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/7cbafbdfdcca/sciadv.abj8658-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/2786c6b60ad0/sciadv.abj8658-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/74c9fcc8fbf2/sciadv.abj8658-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/bc320babb124/sciadv.abj8658-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/295e/8967231/92538b54994c/sciadv.abj8658-f6.jpg

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