ArticleCellular & molecular biology letters2024
APOE2 protects against Aβ pathology by improving neuronal mitochondrial function through ERRα signaling.
Article in Cellular & molecular biology letters, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Older adult APOE4 mice exhibit modest immunometabolic adaptation following microglial APOE2 replacement.Neurobiology of aging · 2026Article
- Estrogen Withdrawal-Induced Cognitive Impairment in Menopausal Women: Mechanisms and Prospects for Integrated Interventions.International journal of molecular sciences · 2026Review
- Organelle stress in NLRP3 inflammasome: a central mediator of neurodegenerative diseases.Molecular neurodegeneration · 2026Review
- Ginkgolide as a Promising Multi-Target Therapeutic for Alzheimer's Disease: Targeting ApoE4 and Beyond.Current pharmaceutical design · 2026Article
- The association between APOE allele variants and inflammatory markers in a large-scale Chinese population.Lipids in health and disease · 2025Article
- Integrating neuroprotection, antioxidative effects, and precision medicine in glaucoma management with bioactive compounds.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2025Review
- Olfactory-Guided Behavior Uncovers Imaging and Molecular Signatures of Alzheimer's Disease Risk.Brain sciences · 2025Article
- Smelling the Risk: Early Olfactory Deficits, Brain Networks, and Blood Markers of Alzheimer's Disease Risk in Humanized APOE Mice.bioRxiv : the preprint server for biology · 2025Article
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13 authors.
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Abstract
backgroundAlzheimer'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.
methodsWe 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.
resultsThe 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.
conclusionsAPOE2 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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