Probiotic Bifidobacterium breve decreases Aβ production via the upregulation of ADAM10 level and attenuates microglia activation in an APP knock‐in mouse model of Alzheimer’s disease

Abstract

Probiotics supplementation reinstates microbiome diversity and improves brain function, including memory and learning abilities, although the molecular mechanisms have not been fully elucidated. In the current study, we investigated the effects of orally supplemented Bifidobacterium breve MCC1274 (B. breve MCC1274, synonym B. breve A1) on memory impairment and Alzheimer's disease (AD) pathogenesis in amyloid precursor protein knock-in (APP-KI) mice, (AppNL-G-F ).Three-month-old AppNL-G-F mice were orally supplemented with B. breve MCC1274 for four months. Novel object recognition test was used to evaluate memory-ameliorating effect of B. breve MCC1274. Amyloid plaques, Aβ levels, amyloid precursor protein (APP) and its processing enzymes, its metabolic products, and glial activity were assessed by immunohistochemistry, Aβ ELISA, Western blotting, and immunofluorescence staining. The mRNA expression levels of neuroinflammatory cytokines determined by quantitative RT-PCR analysis.Oral supplementation of B. breve MCC1274 rescued cognitive deficits in AppNL-G-F mice and down-regulated hippocampal Aβ40 and Aβ42 levels via the enhancement of non-amyloidogenic processing of APP, resulting from the enhancement of a-disintegrin and metalloproteinase 10 (ADAM10) protein level. Moreover, oral supplementation of B. breve MCC1274 activated the ERK/HIF-1α signaling pathway, which is responsible for the enhancement of ADAM10 level. In addition, oral supplementation ofB. breve MCC1274 attenuated microglial activation, which in turn led to down-regulation of the neuroinflammatory cytokines such as interleukin-6 (IL-6) and IL-1β mRNA expression levels in the brain. Moreover, B. breve MCC1274 supplementation increased postsynaptic protein levels in the hippocampus.Our study sheds light on the mechanism by which oral supplementation of B. breve MCC1274 reduced Aβ production and deposition through the enhancement of ERK-HIF-1α-ADAM10 signaling pathway, consequently rescuing cognitive deficits. Therefore, our findings suggest that oral supplementation of B. breve MCC1274 could be used as a potential therapy for preventing AD progression.