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

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder with varying susceptibility linked to apolipoprotein E (APOE) genotypes.
• The APOE2 allele is associated with reduced AD risk, suggesting a potential neuroprotective role, though its mechanisms remain unclear.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying the neuroprotective effects of APOE2 in Alzheimer's disease.
• To investigate the role of APOE2 in neural mitochondrial function and cellular energy metabolism.

Main Methods:

• Analysis of single-nucleus and bulk RNA sequencing data from APOE2 and APOE3 carriers (ROSMAP cohort).
• Validation in SH-SY5Y cells and AD model mice, assessing mitochondrial function and cognitive behaviors.
• Investigated interactions between APOE2 and estrogen-related receptor alpha (ERRα).

Main Results:

• APOE2 is strongly associated with cellular stress and energy metabolism, particularly in neurons, and this is exacerbated by beta-amyloid (Aβ).
• APOE2 overexpression mitigates Aβ-induced mitochondrial dysfunction and reactive oxygen species generation.
• APOE2 may exert protective effects by interacting with estrogen-related receptor alpha (ERRα), which itself demonstrates mitochondrial protective effects and improves cognitive function in AD models.

Conclusions:

• APOE2 enhances neural mitochondrial function through the activation of ERRα signaling.
• This ERRα pathway activation represents a potential therapeutic strategy for Alzheimer's disease.