The inhibitory effects and mechanisms of milk-derived MFG-E8 on Aβ-induced inflammatory responses in BV-2 microglia

β-Amyloid (1-42) (Aβ₄₂) can induce excessive activation of microglia, resulting in exacerbated neuroinflammation and neuronal damage. Milk fat globule-epidermal growth factor-8 (MFG-E8) is known to regulate Aβ₄₂-induced neurotoxicity and inflammatory responses via multiple signaling pathways. However, insufficient secretion of endogenous MFG-E8 may lead to autoimmunity in the central nervous system and the accumulation of apoptotic cells. In this study, we systematically investigated the inhibitory effects and potential mechanisms of exogenously administered milk-derived MFG-E8 (M-MFG-E8) on Aβ₄₂-induced inflammation in BV-2 microglia using various techniques, including cell morphology analysis, immunofluorescence staining, ELISA, qRT-PCR, and Western blot assays. The results demonstrated that Aβ₄₂ significantly increased the expression levels of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) in BV-2 microglia, whereas treatment with M-MFG-E8 effectively reversed these inflammatory responses. Furthermore, Aβ₄₂ stimulation increased the secretion of pro-inflammatory cytokines (TNF-α, IL-1β) and the expression of the M1 marker cluster of differentiation 86 (CD86), while suppressing the anti-inflammatory factors (arginase-1 (Arg-1), interleukin-10 (IL-10)) and the M2 marker cluster of differentiation 206 (CD206) in microglia. In contrast, M-MFG-E8 treatment promoted the polarization of microglia from the M1 to the M2 phenotype. Notably, M-MFG-E8 also inhibited the Aβ₄₂-induced upregulation of CD68, whereas M-MFG-E8 alone did not elicit this effect. Finally, our findings suggest that exogenous M-MFG-E8 may exert anti-inflammatory actions through the modulation of the NF-κB and PI3K/Akt pathways, providing new insights into neuronal cell repair and the development of functional foods.