Alzheimer’s Amyloid-β Accelerates Cell Senescence and Suppresses SIRT1 in Human Neural Stem Cells

Author:

Li Rongyao12,Li Yi123,Zuo Haowei1,Pei Gang245ORCID,Huang Shichao2,Hou Yujun1ORCID

Affiliation:

1. Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China

2. State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China

3. The First Affiliated Hospital, Zhejiang University School of Medicine, and Liangzhu Laboratory of Zhejiang University, Hangzhou 310000, China

4. Shanghai Key Laboratory of Signaling and Disease Research, Collaborative Innovation Center for Brain Science, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China

5. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100100, China

Abstract

As a lifelong source of neurons, neural stem cells (NSCs) serve multiple crucial functions in the brain. The senescence of NSCs may be associated with the onset and progression of Alzheimer’s disease (AD). Our study reveals a noteworthy finding, indicating that the AD-associated pathogenic protein amyloid-β (Aβ) substantially enhances senescence-related characteristics of human NSCs. These characteristics encompass the enhanced expression of p16 and p21, the upregulation of genes associated with the senescence-associated secretory phenotype (SASP), increased SA-β-gal activity, and the activation of the DNA damage response. Further studies revealed that Aβ treatment significantly downregulates the SIRT1 protein which plays a crucial role in regulating the aging process and decreases downstream PGC-1α and FOXO3. Subsequently, we found that SIRT1 overexpression significantly alleviates a range of Aβ-induced senescent markers in human NSCs. Taken together, our results uncover that Aβ accelerates cellular senescence in human NSCs, making SIRT1 a highly promising therapeutic target for senescent NSCs which may contribute to age-related neurodegenerative diseases, including AD.

Funder

Lingang Laboratory

National Natural Science Foundation of China

Natural Science Foundation of Shanghai

National Science Foundation for Young Scientists of China

National Key Research and Development Program of China

Strategic Priority Research Program of the Chinese Academy of Sciences

Fundamental Research Funds for the Central Universities

Publisher

MDPI AG

Subject

Molecular Biology,Biochemistry

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