APOE4 may reduce mitochondrial cleanup by disrupting antioxidant and recycling signals

APOE4 neurons fail to activate PINK1/Parkin-dependent mitophagy under stress, compromising mitochondrial quality control.

• APOE4 is associated with mitochondrial dysfunction in neurons, particularly in Alzheimer's disease.
• The Nrf2-PINK1/Parkin pathway is identified as failing in APOE4 neurons compared to APOE3 neurons.
• Impaired Nrf2 signaling and antioxidant defenses further exacerbate the mitophagy defect in APOE4 neurons.
• In vivo studies show that APOE4 mice experience an age-dependent decline in this mitochondrial quality control pathway.
• The collapse of this pathway correlates with increasing mitochondrial dysfunction and disrupted communication between mitochondria and the nucleus.
• Pharmacological activation of Nrf2 or PINK1 can restore mitochondrial clearance, suggesting potential therapeutic targets.

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