Milk Fat Globule Membrane Supplementation Attenuates Cognitive Impairment in APP/PS1 Mice via Suppressing Neuroinflammation in a Gut Microbiota-Mediated Serum Resolvin D1/Anandamide Manner

Abstract

The gut microbiota is crucial in Alzheimer's disease (AD) progression. This study investigated the effects of milk fat globule membrane (MFGM) on AD-related cognitive deficits and mechanisms involving the gut microbiota–brain axis using APP/PS1 mice. Behavior, physiological indicators, neuroinflammation, and microRNAs (miRNAs) in the hippocampus were examined. Then, serum differential metabolites were explored and used to evaluate anti-neuroinflammatory and neuroprotective effects in vitro. To further clarify the reasons for alterations in serum metabolites, the role of MFGM on gut microbiota was explored. Then, APP/PS1 mice (ADCOH) were co-housed with MFGM-fed APP/PS1 mice (AD+MFGMCOH) to allow microbiota transfer via coprophagy. MFGM mitigated learning and memory deficits, neuronal damage, synaptic dysfunction, and blood–brain barrier leakage, associated with suppression of β-amyloid (Aβ) accumulation and Tau phosphorylation (p-TauSer396). It alleviated neuroinflammation via suppressing expression of inflammatory factors, microglial activation marker ionized calcium-binding adaptor molecule 1 (IBA-1) and NLRP3 pathway, which might be correlated with the modulation of miRNA profile in the hippocampus. Moreover, metabolomic analysis identified resolvin D1 (RVD1) and anandamide (AEA) were enriched due to MFGM supplementation. These metabolites regulated miRNAs, suppress neuroinflammation via inhibiting inflammatory factors, IBA-1 expression, and NLRP3 pathway in BV2 cells, and attenuate p-TauSer396 in SH-SY5Y cells. Furthermore, MFGM modulated gut microbiota and effects of MFGM on cognitive impairment were proved to be associated with increased serum RVD1 and AEA mediated by gut microbiota. In summary, MFGM attenuated AD-related cognitive impairment through suppressing neuroinflammation, correlated with the modulation of gut microbiota-serum RVD1/AEA–brain axis, indicating it could delay AD progression.