Integrated in-silico and in-vitro assessments of HDAC6 inhibitor efficacy in mitigating amyloid beta pathology in Alzheimer's disease

Alzheimer's disease, marked by memory loss and cognitive decline, is associated with amyloid-beta (A beta) peptide accumulation in the brain. The enzyme neprilysin (NEP), crucial for A beta degradation, decreases with age and in sporadic Alzheimer's disease, leading to increased A beta build-up. This study hypothesized the targeting of enzyme HDAC6, believed to influence NEP activity. An in-silico study was conducted using an FDA-approved drug database, with the focus on their interaction with the HDAC6 structure. Among tested ligands, Panobinostat showed the most favourable interaction with HDAC6. In-vitro experiments on the SH-SY5Y neuronal cell line confirmed these findings, with Panobinostat inhibiting HDAC6, enhancing NEP levels, and reducing A beta load. The study suggests Panobinostat as a potential Alzheimer's therapeutic agent, mitigating A beta accumulation via NEP upregulation. Further research is required for comprehensive understanding and validation.Communicated by Ramaswamy H. Sarma