Drug Development

Background: Despite some advances in treatment, a cure for Alzheimer's disease (AD) remains elusive. Disease hallmarks include heightened neuroinflammation and oxidative stress, associated with progressive decline in mobility and cognitive functions. Natural compounds provide a valuable reservoir of novel bioactive substances with therapeutic potential, fewer side effects, and increased affordability. The plant-derived tannin 1,2,3,4,6-Penta-O-Galloyl-β-D-Glucose (β-PGG) displays potent antioxidant, anti-inflammatory, and neuroprotective properties in vitro, but in vivo evidence is limited. This study assesses the dose-dependent efficacy and therapeutic mechanisms of β-PGG in mitigating age-dependent mobility deficits in a Drosophila melanogaster model of AD.

Method: A fruit fly line overexpressing the human amyloid precursor protein (hAPP) and β-site APP-cleaving enzyme (hBACE), in neurons was used as AD model. Newly eclosed flies were supplemented with 0, 5, or 10µM β-PGG and locomotion was assessed at 7, 14, 21, and 30 days via a negative geotaxis assay. The number of flies passing 2-, 4-, and 8 cm marks in 10 seconds was recorded by genotype, sex, age, and treatment. Oxidative stress sensitivity was measured by quantifying 48-hour survival to paraquat exposure. Flies were homogenized to determine levels of β-PGG metabolites by LC/MS/MS. Data were analyzed via a two-way ANOVA to test the effects of genotype, treatment and their interaction in young (7- and 14-days old) and old (21- and 30 days old) flies.

Result: Young non-supplemented AD females (p<0.0001) and males (p<0.0001) moved significantly slower than controls. β-PGG significantly ameliorated locomotion deficits in young AD flies. AD females (p<0.0001) and AD males (p<0.0001) supplemented with 10µM β-PGG were significantly less movement impaired than their non-treated counterparts. Regardless of genotype, old females supplemented with 10µM β-PGG were significantly faster than untreated cohorts (p<0.05). Conversely, old AD but not control males supplemented with 10µM β-PGG were significantly less movement impaired than their untreated counterparts (p<0.0001). At 48 hours, 2-week β-PGG supplementation significantly improved survival to paraquat among control females but not in males (p<0.01).

Conclusion: Our findings provide strong evidence that β-PGG supplementation mitigates age-associated mobility deficits in our preclinical model of AD. Benefits from this supplementation may delay physiological aging in a sex-specific manner.