iPLA2ß loss leads to age-related cognitive decline and neuroinflammation by disrupting neuronal mitophagy.
J Neuroinflammation
; 21(1): 228, 2024 Sep 18.
Article
em En
| MEDLINE
| ID: mdl-39294744
ABSTRACT
BACKGROUND:
During brain aging, disturbances in neuronal phospholipid metabolism result in impaired cognitive function and dysregulation of neurological processes. Mutations in iPLA2ß are associated with neurodegenerative conditions that significantly impact brain phospholipids. iPLA2ß deficiency exacerbates mitochondrial dysfunction and abnormal mitochondrial accumulation. We hypothesized that iPLA2ß contributes to age-related cognitive decline by disrupting neuronal mitophagy.METHODOLOGY:
We used aged wild-type (WT) mice and iPLA2ß-/- mice as natural aging models to assess cognitive performance, iPLA2ß 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 iPLA2ß, we employed adeno-associated virus (AAV)-mediated iPLA2ß overexpression in aged mice and re-evaluated these parameters.RESULTS:
Our findings revealed a significant reduction in iPLA2ß levels in the prefrontal cortex of aged brains. Notably, iPLA2ß-deficient mice exhibited impaired learning and memory. Loss of iPLA2ß 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 iPLA2ß 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 iPLA2ß loss in the PFC leads to cognitive decline through the disruption of mitophagy. These findings highlight the potential of targeting iPLA2ß to ameliorate age-related neurocognitive disorders.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Envelhecimento
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Fosfolipases A2 do Grupo VI
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Disfunção Cognitiva
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Mitofagia
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Doenças Neuroinflamatórias
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Neurônios
Limite:
Animals
Idioma:
En
Revista:
J Neuroinflammation
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China