A Niacin-α-Lipoic Acid Hybrid Ameliorates Alzheimer's Disease Pathology in Mouse Models

Alzheimer's disease (AD) is the most common neurodegenerative disease with a rapid growth of patients worldwide in the aging era. Therefore, there is an urgent need to develop novel drugs for AD. Niacin and α-lipoic acid have been reported to exhibit therapeutic potential in AD through distinct biological activities, including GPR109A/HCAR2 agonism and antioxidant effects, respectively. N2L, a hybrid molecule derived from α-lipoic acid and niacin and a known GPR109A/HCAR2 agonist, has previously been reported to possess lipid-regulating, antiatherosclerotic, and ferroptosis-inhibitory properties. N2L is superior to niacin and/or lipoic acid alone due to its longer half-life and the absence of flushing side effects. In this study, we evaluated the anti-AD efficacy of N2L in male mice, including both APP/PS1 transgenic familial AD mice and acrolein-induced sporadic AD mice on the same C57BL/6 background. N2L significantly attenuated amyloid-β deposition, tau hyperphosphorylation, glial activation, synaptic degeneration, and ferroptosis in N2L-treated AD mice brains. Additionally, N2L increased the relative abundance of beneficial gut microbial taxa, including Lactobacillus, Bifidobacterium, and Faecalibaculum, suggesting a potential modulation of the microbiota-gut-brain axis. These findings demonstrate that N2L exerts multifaceted protective effects against AD-related pathological alterations and support its further development as a potential therapeutic candidate for AD.