Metabolic Reprogramming of Microglia Enhances Proinflammatory Cytokine Release through EphA2/p38 MAPK Pathway in Alzheimer’s Disease

Abstract

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.

Futoquinol improves Aβ25–35‐induced memory impairment in mice by inhibiting the activation of p38MAPK through the glycolysis pathway and regulating the composition of the gut microbiota

“…Glycolysis can regulate Aβ 1–42 ‐induced cell inflammation through the p38MAPK signaling pathway (X. Ma et al, 2022). The levels of glycolysis and p‐p38MAPK proteins in the brains of the mice were detected.…”

“…Glycolysis can regulate Aβ 1-42 -induced cell inflammation through the p38MAPK signaling pathway (X. Ma et al, 2022). The results showed that Fut and PK significantly reduced the levels of HK II, p-p38MAPK proteins, LD, and the levels of IL-1β, IL-6, and TNF-α in the brain and serum of mice.…”

“…Fut inhibited the glycolysis and the activation of p38MAPK induced by Aβ 25-35 in miceGlycolysis can regulate Aβ 1-42 -induced cell inflammation through the p38MAPK signaling pathway (X Ma et al, 2022)…”

Multiomics profiling of human plasma and cerebrospinal fluid reveals ATN‐derived networks and highlights causal links in Alzheimer's disease

“…[40][41][42] AD PRS was associated with a different lipid class, which are the plasmalogen phosphatidylethanolamines. 43,44 The protein EFNA2 45 was associated to both MCI converter and AD PRS.…”

Multiomics profiling of human plasma and CSF reveals ATN derived networks and highlights causal links in Alzheimer’s disease

“…Interestingly APOE and MCI conversion status were correlated to PCSK7 and sphingomyelins SMs have been previously associated with cognitive progression in AD [41-43]. Furthermore, the integration of AD PRS showed that phosphatidylethanolamines [44, 45] and EFNA2 [46] were associated to both (MCI converter and AD PRS), with potential as early targets.…”