Therapeutic potential of dual HDAC6/SIRT2 inhibition in Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by hallmark pathological changes such as amyloid β (Aβ) plaques, neurofibrillary tangles (NFTs) due to tau hyperphosphorylation, and neuroinflammation. Current therapeutic approaches focusing on single-target strategies exhibit limited efficacy, necessitating the exploration of novel multi-target approaches. Histone deacetylase 6 (HDAC6) and SIRT2, as two types of cytosolic histone deacetylases, have emerged as promising targets for AD treatment. HDAC6 plays a role in tau protein phosphorylation, while SIRT2 is involved in Aβ production. Both enzymes regulate microtubule proteins, impacting the formation of NFTs and Aβ plaques. Inhibition of HDAC6 reduces tau hyperphosphorylation, improves microtubule stability, and mitigates neuroinflammation, whereas SIRT2 inhibition attenuates Aβ accumulation and neuroinflammation. Recent studies indicate that dual-targeted inhibition of HDAC6 and SIRT2 may exhibit synergistic effects, suggesting it as a promising strategy for AD treatment. This review summarizes the biological roles of HDAC6 and SIRT2 in AD pathology and examines the development of dual-target inhibitors. It also discusses the challenges, including selectivity and toxicity, emphasizing that the development of combined HDAC6 and SIRT2 inhibitors represents a new direction for future AD treatment.