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ApoE4 attenuates autophagy via FoxO3a repression in the brain.

ABSTRACT: Apolipoprotein E (ApoE) plays multiple roles in lipid transport, neuronal signaling, glucose metabolism, mitochondrial function, and inflammation in the brain. It is also associated with neurodegenerative diseases, and its influence differs depending on the isoform. In particular, the ε4 allele of APOE is the highest genetic risk factor for developing late-onset Alzheimer's disease (AD). However, the mechanism by which ApoE4 contributes to the pathogenesis of AD remains unclear. We investigated the effect of ApoE4 on autophagy in the human brains of ApoE4 carriers. Compared to non-carriers, the expression of FoxO3a regulating autophagy-related genes was significantly reduced in ApoE4 carriers, and the phosphorylation level of FoxO3a at Ser253 increased in ApoE4 carriers, indicating that FoxO3a is considerably repressed in ApoE4 carriers. As a result, the protein expression of FoxO3a downstream genes, such as Atg12, Beclin-1, BNIP3, and PINK1, was significantly decreased, likely leading to dysfunction of both autophagy and mitophagy in ApoE4 carriers. In addition, phosphorylated tau accumulated more in ApoE4 carriers than in non-carriers. Taken together, our results suggest that ApoE4 might attenuate autophagy via the repression of FoxO3a in AD pathogenesis. The regulation of the ApoE4-FoxO3a axis may provide a novel therapeutic target for the prevention and treatment of AD with the APOE4 allele.

SUBMITTER: Sohn HY

PROVIDER: S-EPMC8413297 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundSeawater drowning is the major cause of accidental injury and death. The current treatment could not essentially block the source of the damage due to the complex etiology. Therefore, it is urgent to clarify the detailed mechanisms and find effective therapeutic approaches.MethodsWe performed in vitro experiments to evaluate the damage of seawater drowning to lung epithelial cells. FACS, immunofluorescent staining, and western blot were used to detect the apoptosis. CCK-8 assay, Ki67 staining, and cell cycle analysis were used to assess the proliferation. The cytokine expression was determined by qRT-PCR and ELISA. Western blot and reporter assay were used for regulation mechanism study. For neutrophils development, Transwell assay and FACS were used for further investigation. Besides, in vivo study was performed with the seawater drowning model in rats.ResultsIn this study, we found that seawater drowning induced mitochondria damage, which further accelerated epithelial cell apoptosis and repressed cell proliferation. Administration of ghrelin attenuated the mitochondria damage via reducing ROS generation, decreasing the concentration of calcium ion and ceremide, and promoting ATP production. Besides, exogenous ghrelin also rescued the cell survival inhibited by seawater simulants. Mechanically, ghrelin retrieved the influence of seawater via inhibiting NF-κB signaling activation, and agonist of NF-κB could offset the function of ghrelin. Besides, ghrelin reduced the expression of inflammatory factors and chemokines responsible for neutrophils activation and recruitment, by which ghrelin suppressed the immune response. The further in vivo experiments also indicated that ghrelin treatment restored the apoptosis promotion and inflammation activation function of seawater simulants, and further alleviated the lung tissue injury.ConclusionsOur study revealed the dual effect of ghrelin on seawater drowning induced lung injury via damage protection and immune repression, providing new insights into drowning injury pathogenesis and therapeutic strategies.

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ApoE4 attenuates autophagy via FoxO3a repression in the brain.

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