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

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Ning, Zhiyuan, Liu, Ying, Wan, Mengyao, Zuo, You, Chen, Siqi, Shi, Zhongshan, Xu, Yongteng, Li, Honghong +5 more·2024·Cellular & Molecular Biology Letters
DOI 10.1186/s11658-024-00600-xPMC PMC11170814
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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.

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  • These findings align with studies showing that E2 supports efficient lipid turnover, mitochondrial function, and resilience to inflammatory stress.

    “These findings align with studies showing that E2 supports efficient lipid turnover, mitochondrial function, and resilience to inflammatory stress”

    From Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement (2027) · cites this paper as Ning et al., 2024

    The Results (APOE2 pathway-level alterations; page unavailable) report enhanced triglyceride catabolism and changes in cholesterol metabolism in APOE2 carriers, while the Abstract Results report improved mitochondrial function and reduced reactive oxygen species in Aβ-stimulated cells. These findings support the lipid-metabolism and mitochondrial portions, though they do not establish efficient lipid turnover broadly. The Results also report altered immune-related pathways, but do not show resilience to inflammatory stress. (LLM, conf=0.86)

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Sorted by citations

Authors
Ning, Z., Liu, Y., Wan, M., Zuo, Y., Chen, S., Shi, Z., Xu, Y., Li, H., Ko, H., Zhang, J., Xiao, S., Guo, D., & Tang, Y.
Affiliations
  • Sun Yat-sen University (CN)
  • Chinese University of Hong Kong (HK)
  • Fujian Medical University (CN)
Corresponding author
  • Xiao, Songhua
  • Guo, Daji
  • Tang, Yamei
ORCID
Venue
Cellular & Molecular Biology Letters
Publisher
Springer Science and Business Media LLC
Published
2024-06-12
Volume
29
Issue
1
Pages
87-87
ISSN
  • 1425-8153 (ISSN-L)
  • 1689-1392
DOI
10.1186/s11658-024-00600-x
PMC
PMC11170814
OpenAlex
W4399572659
Cited by
20
References
13
Citations by year
2026: 12 · 2025: 7 · 2024: 1
FWCI
5.17
Type
journal article
Language
en
Open access
Licence
Locations
  • Cellular & Molecular Biology Letters (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (81925031, 81820108026, 82103775, 82003389)
  • Guangzhou Science and Technology Program key projects (202007030001)
  • China Postdoctoral Science Foundation (2023M734052, 2023T160756, 2022M723589)
  • GuangDong Basic and Applied Basic Research Foundation (2021A1515010209)
  • Sun Yat-Sen Clinical Research Cultivating Program (SYS-Q-202208)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
APOE2, Alzheimer's disease, amyloid-beta, mitochondrial dysfunction, estrogen-related receptor alpha, reactive oxygen species, energy metabolism, neuronal stress, PSD-95, cognitive impairment, APOE ε4, neuroprotection
MeSH terms
ERRalpha Estrogen-Related Receptor, Alzheimer Disease, Animals, Apolipoproteins E, Disease Models, Animal, Female, Humans, Male, Mitochondria, Neurons, Receptors, Estrogen, Signal Transduction, Amyloid beta-Peptides, Reactive Oxygen Species, Cell Line, Tumor, Mice, Apolipoprotein E2

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