2. Academic Validation
  3. APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling

APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling

  • Cell Mol Biol Lett. 2024 Jun 12;29(1):87. doi: 10.1186/s11658-024-00600-x.
Zhiyuan Ning # 1 2 3,  Ying Liu # 1 2 3,  Mengyao Wan # 1 2 3,  You Zuo 1 2,  Siqi Chen 2 3,  Zhongshan Shi 1 2,  Yongteng Xu 1 2,  Honghong Li 1 2,  Ho Ko 4,  Jing Zhang 5,  Songhua Xiao 6 7,  Daji Guo 8 9 10,  Yamei Tang 11 12 13 14 15
Affiliations

Affiliations

  • 1 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
  • 2 Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
  • 3 Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China.
  • 4 Division of Neurology, Department of Medicine and Therapeutics & Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
  • 5 Department of Neurology, Fujian Medical University Union Hospital, Fujian Key Laboratory of Molecular Neurology and Institute of Neuroscience, Fujian Medical University, Fuzhou, China.
  • 6 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. xiaosh@mail.sysu.edu.cn.
  • 7 Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. xiaosh@mail.sysu.edu.cn.
  • 8 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. guodj5@mail.sysu.edu.cn.
  • 9 Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. guodj5@mail.sysu.edu.cn.
  • 10 Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China. guodj5@mail.sysu.edu.cn.
  • 11 Department of Neurology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. tangym@mail.sysu.edu.cn.
  • 12 Brain Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. tangym@mail.sysu.edu.cn.
  • 13 Nanhai Translational Innovation Center of Precision Immunology, Sun Yat-Sen Memorial Hospital, Foshan, 528200, China. tangym@mail.sysu.edu.cn.
  • 14 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China. tangym@mail.sysu.edu.cn.
  • 15 Guangdong Province Key Laboratory of Brain Function and Disease, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, 510080, China. tangym@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 38867189 DOI: 10.1186/s11658-024-00600-x
Abstract

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear.

Methods: We analyzed single-nucleus RNA Sequencing and bulk RNA Sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively.

Results: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aβ). Moreover, APOE2 overexpression alleviates Aβ1-42-induced mitochondrial dysfunction and reduces the generation of Reactive Oxygen Species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aβ1-42-stimulated SH-SY5Y cells. Additionally, ERRα Agonist treatment improve the cognitive performance of Aβ injected mice in both Y maze and novel object recognition tests. ERRα Agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice.

Conclusions: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.

Keywords

Alzheimer's disease; Apolipoprotein E; Beta-amyloid (Aβ); ESRRA; Mitochondria; Neuron.

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