Background: The activation of microglia and neuroinflammation has been implicated in the pathogenesis of Alzheimer’s disease (AD), but the exact roles of microglia and the underlying mechanisms remain unclear. Objective: To clarify how the metabolic reprogramming of microglia induce by amyloid-β (Aβ)1-42 to affect the release of proinflammatory cytokines in AD. Methods: MTS assay was used to detect the viability of BV2 cells treated with different concentrations of Aβ1-42 for different periods of time. The expression levels of proinflammatory cytokines were determined by qRT-PCR and western blot assay in BV2 cells and hippocampus of mice. RNA sequencing was applied to evaluate the gene expression profiles in response to HK2 knockdown in BV2 cells treated with Aβ1-42. Results: Low concentrations of Aβ1-42 increased the viability of BV2 cells and promoted the release of proinflammatory cytokines, and this process is accompanied by increased glycolysis. Inhibition of glycolysis significantly downregulated the release of proinflammatory cytokines in BV2 cells and hippocampus of mice treated with Aβ1-42. The results of RNA sequencing revealed the expression of chemokine ligand 2 (Cxcl2) and ephrin receptor tyrosine kinase A2 (EphA2) were significantly downregulated when knocked down HK2 in BV2 cells. Subsequently, the expression of proinflammatory cytokines was downregulated in BV2 cell after knocking down EphA2. Conclusion: This study demonstrated that EphA2/p38 MAPK pathway is involved the release of proinflammatory cytokines in microglia induced by Aβ1-42 in AD, which is accompanied by metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis.

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