BAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer's disease pathology

Liansheng Zhang; Yun Qian; Jie Li; Xuan Zhou; He Xu; Jie Yan; Jialing Xiang; Xiang Yuan; Beicheng Sun; Sangram S Sisodia; Yong-Hui Jiang; Xiaohua Cao; Naihe Jing; Anning Lin

doi:10.1016/j.isci.2021.102942

BAD-mediated neuronal apoptosis and neuroinflammation contribute to Alzheimer's disease pathology

iScience. 2021 Aug 4;24(9):102942. doi: 10.1016/j.isci.2021.102942. eCollection 2021 Sep 24.

Authors

Liansheng Zhang^{1

2

3}, Yun Qian¹, Jie Li^{1

3

4}, Xuan Zhou⁵, He Xu^{1

4}, Jie Yan⁶, Jialing Xiang⁷, Xiang Yuan^{1

2

3}, Beicheng Sun⁸, Sangram S Sisodia^{9

10}, Yong-Hui Jiang¹¹, Xiaohua Cao⁵, Naihe Jing^{1

4

12

13}, Anning Lin^{2

3

9

14}

Affiliations

¹ The State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences; University of Chinese Academy of Sciences, Shanghai 200031, China.
² Institute of Modern Biology, Nanjing University, Nanjing 210023, China.
³ Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.
⁴ School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
⁵ Key Laboratory of Brain Functional Genomics, Ministry of Education, School of Life Sciences, East China Normal University, Shanghai 200062, China.
⁶ The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allery & Clinical Immunology, Guangzhou Medical University, Guangzhou, Guangdong 510260, China.
⁷ Department of Biological and Chemical Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA.
⁸ Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China.
⁹ Department of Neurobiology, The University of Chicago, Chicago, IL 60637, USA.
¹⁰ The Microbiome Center, The University of Chicago, Chicago, IL 60637, USA.
¹¹ Department of Pediatrics and Neurobiology, Duke University School of Medicine, Durham, NC 27710, USA.
¹² CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
¹³ Center of Cell Lineage and Atlas, Guangzhou Regenerative Medicine and Health Guangdong Laboratory (GRMH-GDL), Guangzhou 510005, China.
¹⁴ Grossman Institute for Neuroscience, Quantitative Biology, and Haman Behavior, The University of Chicago, Chicago, IL 60637, USA.

Abstract

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. However, the underlying molecular mechanism is incompletely understood. Here we report that the pro-apoptotic protein BAD as a key regulator for neuronal apoptosis, neuroinflammation and Aβ clearance in AD. BAD pro-apoptotic activity is significantly increased in neurons of AD patients and 5XFAD mice. Conversely, genetic disruption of Bad alleles restores spatial learning and memory deficits in 5XFAD mice. Mechanistically, phosphorylation and inactivation of BAD by neurotropic factor-activated Akt is abrogated in neurons under AD condition. Through reactive oxygen species (ROS)-oxidized mitochondrial DNA (mtDNA) axis, BAD also promotes microglial NLRP3 inflammasome activation, thereby skewing microglia toward neuroinflammatory microglia to inhibit microglial phagocytosis of Aβ in AD mice. Our results support a model in which BAD contributes to AD pathologies by driving neuronal apoptosis and neuroinflammation but suppressing microglial phagocytosis of Aβ, suggesting that BAD is a potential therapeutic target for AD.

Keywords: Molecular biology; Molecular neuroscience; Neuroscience.

Abstract

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