BT-11 repurposing potential for Alzheimer's disease and insights into its mode of actions

Neuroinflammation is a key pathological hallmark of Alzheimer's disease (AD). Investigational and FDA approved drugs targeting inflammation already exist, thus drug repurposing for AD is a suitable approach. BT-11 is an investigational drug that reduces inflammation in the gut and improves cognitive function. BT-11 is orally active and binds to lanthionine synthetase C-like 2 (LANCL2), a glutathione-s-transferase, thus potentially reducing oxidative stress. We investigated the effects of BT-11 long-term treatment on the TgF344-AD rat model. BT-11 reduced hippocampal-dependent spatial memory deficits, Aβ plaque load and neuronal loss in males, and mitigated microglia numbers in females. BT-11 treatment led to hippocampal transcriptomic changes in signaling receptor, including G-protein coupled receptor pathways. We detected LANCL2 in hippocampal nuclear and cytoplasmic fractions with potential different post-translational modifications, suggesting distinct functions based on its subcellular localization. LANCL2 was present in oligodendrocytes, showing a role in oligodendrocyte function. To our knowledge, these last two findings have not been reported. Overall, our data suggest that targeting LANCL2 with BT-11 improves cognition and reduces AD-like pathology by potentially modulating G-protein signaling and oligodendrocyte function. Our studies contribute to the field of novel immunomodulatory AD therapeutics, and merit further research on the role of LANCL2 in this disease.