Oral Delivery of TDCA Attenuates Cognitive Decline and Amyloid Pathology in Alzheimer’s Disease Model.

Alzheimer's disease (AD) is characterized by cognitive impairment, amyloid-beta (Aβ) plaque accumulation, and neuroinflammation, with current treatments offering limited efficacy in altering disease progression. This study investigates the therapeutic potential of taurodeoxycholic acid (TDCA), a secondary bile acid with anti-inflammatory properties, as an orally administered treatment for AD. In a 10-week study, TDCA was orally administered to 5xFAD transgenic mice, a model of familial AD, at a dose optimized for therapeutic benefit. Cognitive performance was evaluated using Morris Water Maze (MWM) and Novel Object Recognition (NOR) tests, while amyloid plaque deposition and neuronal integrity were assessed through Thioflavin-S staining and NeuN immunostaining, respectively. TDCA-treated 5xFAD mice demonstrated significant improvements in spatial learning and memory in MWM and NOR tests compared to vehicle-treated controls. Treatment also resulted in a notable reduction in Aβ plaque burden, preserved NeuN-positive neurons, and decreased markers of neuroinflammation. By modulating microglial activity and suppressing the NLRP3 inflammasome, TDCA reduced pro-inflammatory cytokine secretion (IL-1β, IL-18) and enhanced Aβ clearance via restored scavenger receptor A (SRA) expression. These findings highlight TDCA as a promising oral therapeutic candidate for AD, capable of attenuating cognitive decline and amyloid pathology while targeting key neuroinflammatory mechanisms