Drug Development

Gut microbiota disruptions have been implicated in Alzheimer's disease (AD) pathogenesis. Lactobacillus probiotics have demonstrated therapeutic potential in AD by modulating the gut microbiome, while Lactobacillus postbiotics, soluble factors secreted by live bacteria, confer similar effects with advantages like longer shelf life, lower cost, and reduced infection risk. Evidence of the benefits of postbiotics in AD is limited. This study compares the effectiveness of Lactobacillus probiotics and postbiotics in mitigating behavioral deficits in a Drosophila model of AD.

Flies overexpressing human amyloid β precursor protein and β-site APP cleaving enzyme in neurons served as AD model. Lactobacillus plantarum (Lp) was prepared at 1.0 x 10⁹ CFU/µL in MRS Lactobacilli broth, with the upper 80% of culture supernatant filtered as postbiotic fraction (Lp-PBx). Lp and Lp-PBx were diluted 1:2 in 5% sucrose and administered via capillaries in four 24-hour doses over two weeks. Food intake was recorded. Locomotion and memory were assessed at 14 days. Locomotion was evaluated using a negative geotaxis assay testing flies' ability to cross 8-cm in 10 seconds. Memory was tested through an aversive phototaxic suppression assay, where flies were trained to associate light with an aversive odor. After ten training cycles, flies were tested for dark preference. Data was stratified by sex and analyzed through a two-way ANOVA to test the main effects of genotype, treatment, and their interaction.

Untreated AD males (0.48±0.03 vs 0.80±0.03, p<0.0001) and females (0.39±0.04 vs 0.70±0.04, p<0.0001) exhibited significant mobility impairments compared to controls. However, AD flies fed Lp or Lp-PBx showed restored mobility, climbing at speeds comparable to controls. Specifically, AD males fed Lp (0.73±0.03) or Lp-PBx (0.75±0.03) and females fed Lp (0.61±0.04) or Lp-PBx (0.59±0.04) climbed significantly faster than untreated counterparts (males: 0.48±0.03, p<0.0001; females: 0.39±0.04, p<0.05). While food intake in females was unaffected, males fed Lp ate significantly less than those given Lp-PBx (p=0.0216), regardless of genotype. Memory assays are ongoing.

In summary, our findings suggest Lp-PBx as a viable alternative to Lp for managing mobility deficits in a Drosophila model of AD. Its palatability facilitates administration, making it a practical therapeutic option.