BT-11 targets the LANCL2 pathway to attenuate cognitive deficits and hippocampal pathology in Alzheimer’s transgenic rats

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 of AD. BT-11 (1) reduced spatial memory deficits, and hippocampal Abeta plaque load, and increased neuronal levels in males, and reduced microglia numbers in females, and (2) induced transcriptomic changes in signaling receptor, including G-protein coupled receptor pathways in both males and females, with changes in neurotrophic factors only in males. We detected LANCL2 in hippocampal nuclear and cytoplasmic fractions with potentially different post-translational modifications, suggesting distinct functions based on its subcellular localization. LANCL2 was present in oligodendrocytes, indicating a role in oligodendrocyte function. To our knowledge, these last two findings have not been reported. Overall, our data support that targeting LANCL2 with BT-11 improves cognition and reduces AD-like pathology potentially by modulating G-protein signaling. LANCL2's localization in oligodendrocytes suggest a possible role oligodendrocyte function that warrants further investigation. Our studies contribute to the field of new immunomodulatory AD therapeutics and establish LANCL2 as a promising therapeutic target meriting further mechanistic investigation.