Lactobacilli Probiotics Prevent Amyloid-Beta Fibril Formation In Vitro

Alzheimer's disease (AD) is characterized by the buildup of extracellular aggregated amyloid-β (Aβ) peptides, following sequential enzymatic cleavage of amyloid precursor protein (APP), along with intraneuronal accumulation of hyperphosphorylated Tau proteins (pTau) and subsequent neuronal loss. Despite extensive research, the precise mechanisms underlying Aβ, and Tau-mediated neurodegeneration remain elusive. Inhibiting protein aggregation has been a primary focus for mitigating neuronal toxicity. The gut-brain axis is a potential factor in AD progression, with evidence suggesting that gut-resident bacteria may produce aggregated proteins that contribute to host protein aggregation. Altered gut microbial diversity has also been observed in individuals with AD. Probiotics have emerged as a promising preventative measure against cognitive decline in AD, with several in vivo and clinical trials demonstrating the efficacy of select bacterial strains in slowing AD progression. However, these studies lack direct molecular evidence on the effects of probiotics on Aβ aggregation kinetic. In this study, we conducted bioinformatic and physicochemical assessments, including molecular docking of proteins derived from 13 probiotic strains against Aβ and Tau, identifying four strains predicted to efficiently inhibit Aβ aggregation. Kinetic studies confirmed that both the probiotic formulation and its derived supernatant significantly inhibited the conversion of monomeric Aβ into aggregated forms. To explore bioavailability, we administered the probiotic formulation to healthy individuals and detected its presence in stool samples, demonstrating survival through the gastrointestinal tract. These findings suggest that specific probiotic strains may serve as therapeutic candidates for targeting Aβ aggregation, with further studies warranted to assess their potential clinical utility in AD.