Probiotic Bifidobacterium breve Prevents Memory Impairment Through the Reduction of Both Amyloid-β Production and Microglia Activation in APP Knock-In Mouse1

Abstract

Background: Probiotic supplementation reestablishes microbiome diversity and improves brain function in Alzheimer’s disease (AD); their molecular mechanisms, however, have not yet been fully illustrated. Objective: We investigated the effects of orally supplemented Bifidobacterium breve MCC1274 on cognitive function and AD-like pathologies in AppNL-G-F mice. Methods: Three-month-old AppNL-G-F mice were orally supplemented with B. breve MCC1274 for four months. The short-term memory function was evaluated using a novel object recognition test. Amyloid plaques, amyloid-β (Aβ) levels, Aβ fibril, amyloid-β protein precursor and its processing enzymes, its metabolic products, glial activity, and cell proliferation in the subgranular zone of the dentate gyrus were evaluated by immunohistochemistry, Aβ ELISA, western blotting, and immunofluorescence staining. The mRNA expression levels of pro- and anti-inflammatory cytokines were determined by qRT-PCR analysis. Results: We found that the oral B. breve MCC1 274 supplementation prevented memory impairment in AppNL-G-F mice and decreased hippocampal Aβ levels through the enhancement of the a-disintegrin and metalloproteinase 10 (ADAM10) level. Moreover, administration of the probiotic activated the ERK/HIF-1α signaling pathway responsible for increasing the ADAM10 level and also attenuated microglial activation, which in turn led to reduction in the mRNA expression levels of pro-inflammatory cytokines in the brain. In addition, B. breve MCC1274 supplementation increased the level of synaptic proteins in the hippocampus. Conclusion: Our findings support the possibility that oral B. breve MCC1274 supplementation might be used as a potential preventive therapy for AD progression.

Probiotic Bifidobacterium breve MCC1274 Mitigates Alzheimer’s Disease-Related Pathologies in Wild-Type Mice

“…In contrast to the hippocampus, these protein levels did not change in the cortical extracts between the two groups (Figure 6B). These findings indicate that B. breve MCC1274 supplementation increases the expression of synaptic proteins in WT mice, which is consistent with previous findings that B. breve MCC1274 supplementation increases these synaptic protein levels in App NL-G-F mice [27].…”

“…Unfortunately, their mRNA levels were undetectable, even in the saline-supplemented group (data not shown), possibly because neuroinflammation had not occurred because the mice were still young. These results suggest that B. breve MCC1274 supplementation in WT mice attenuates microglial activation only in the hippocampus, and does not affect reactive astrocytes, which is consistent with previous findings in App NL-G-F mice [27].…”

“…Aβ production in the brain is affected by altered levels of APP and APP-processing enzymes, such as ADAM10, BACE1, and PS1, which are α-secretase, β-secretase, and γ-secretase components, respectively. A previous study demonstrated that oral supplementation with B. breve MCC1274 reduced hippocampal Aβ production in App NL-G-F mice by increasing the ADAM10 levels [27]. Thus, the effect of probiotic supplementation on Aβ levels in WT mice was investigated, and the results showed a significant decrease in soluble Aβ42 levels in the hippocampal extracts of mice supplemented with probiotics compared to those of mice that received saline (Figure 2A).…”

“…B. breve MCC1274 was prepared as previously described [27]. Briefly, B. breve MCC1274 was isolated from infant feces.…”

“…Previous studies demonstrated that oral supplementation with Bifidobacterium breve MCC1274 (B. breve MCC1274) improved cognitive function in both an AD-like mouse model and mild cognitive impairment (MCI) subjects [24,25]. Furthermore, recently, it has been reported that oral supplementation with B. breve MCC1274 for four months mitigated AD-like pathologies in App NL-G-F mice overexpressing humanized Aβ with APP mutations (Swedish (NL), Beyreuther/Iberian (F), and Arctic (G)) without overexpressing APP [26], as indicated by a reduction in amyloidosis, attenuation of microglial activation, and improvement of synaptic plasticity in the hippocampus, which ultimately prevented memory impairment [27]. These studies highlight the therapeutic potential of B. breve MCC1274 in preventing memory impairment and delaying the progression of AD.…”