Jiao_2024_J.Neuroinflammation_21_228

BACKGROUND: During brain aging, disturbances in neuronal phospholipid metabolism result in impaired cognitive function and dysregulation of neurological processes. Mutations in iPLA2beta are associated with neurodegenerative conditions that significantly impact brain phospholipids. iPLA2beta deficiency exacerbates mitochondrial dysfunction and abnormal mitochondrial accumulation. We hypothesized that iPLA2beta contributes to age-related cognitive decline by disrupting neuronal mitophagy. METHODOLOGY: We used aged wild-type (WT) mice and iPLA2beta(-/-) mice as natural aging models to assess cognitive performance, iPLA2beta expression in the cortex, levels of chemokines and inflammatory cytokines, and mitochondrial dysfunction, with a specific focus on mitophagy and the mitochondrial phospholipid profile. To further elucidate the role of iPLA2beta, we employed adeno-associated virus (AAV)-mediated iPLA2beta overexpression in aged mice and re-evaluated these parameters. RESULTS: Our findings revealed a significant reduction in iPLA2beta levels in the prefrontal cortex of aged brains. Notably, iPLA2beta-deficient mice exhibited impaired learning and memory. Loss of iPLA2beta in the PFC of aged mice led to increased levels of chemokines and inflammatory cytokines. This damage was associated with altered mitochondrial morphology, reduced ATP levels due to dysregulation of the parkin-independent mitophagy pathway, and changes in the mitochondrial phospholipid profile. AAV-mediated overexpression of iPLA2beta alleviated age-related parkin-independent mitophagy pathway dysregulation in primary neurons and the PFC of aged mice, reduced inflammation, and improved cognitive function. CONCLUSIONS: Our study suggests that age-related iPLA2beta loss in the PFC leads to cognitive decline through the disruption of mitophagy. These findings highlight the potential of targeting iPLA2beta to ameliorate age-related neurocognitive disorders.