Neuronal C/EBPβ/AEP pathway shortens life span via selective GABAnergic neuronal degeneration by FOXO repression-Reference-Cited by-同舟云学术

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

Published:2022-04 Issue:13 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Xia Yiyuan¹^ORCID,Qadota Hiroshi¹,Wang Zhi-Hao¹,Liu Pai¹²,Liu Xia¹^ORCID,Ye Karen X.³^ORCID,Matheny Courtney J.¹,Berglund Ken⁴^ORCID,Yu Shan Ping⁵^ORCID,Drake Derek⁶,Bennett David A.⁷^ORCID,Wang Xiao-Chuan⁸⁹^ORCID,Yankner Bruce A.⁶,Benian Guy M.¹^ORCID,Ye Keqiang¹¹⁰^ORCID

Affiliation:

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

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

3. Emory College of Arts and Sciences, Emory University, Atlanta, GA 30322, USA.

4. Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA.

5. Department of Anesthesiology, Emory University, Atlanta, GA 30322, USA.

6. Department of Genetics, Harvard Medical School, Boston, MA, USA.

7. Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA.

8. Department of Pathophysiology, Key Laboratory of Ministry of Education of Neurological Diseases, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.

9. Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu 226001, China.

10. Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Shenzhen, China.

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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