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bioRxiv · 10.1101/2024.10.29.620882

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

Birnbaum, E. M.·Xie, L.·Serrano, P.·Rockwell, P.·Figueiredo-Pereira, M. E.
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Abstract

Neuroinflammation is a key pathological hallmark of Alzheimers 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, A{beta} 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.

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Birnbaum, E. M., Xie, L., Serrano, P., Rockwell, P., Figueiredo-Pereira, M. E.. 2024-10-29. BT-11 repurposing potential for Alzheimer's disease and insights into its mode of actions. https://doi.org/10.1101/2024.10.29.620882

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