Small molecules targeting molecular chaperones for tau regulation: Achievements and challenges

Abnormal post-translational modification of microtubule-associated protein Tau (MAPT) is a prominent pathological feature in Alzheimer's disease (AD). Previous research has focused on designing small molecules to target Tau modification, aiming to restore microtubule stability and regulate Tau levels in vivo. However, progress has been hindered, and no effective Tau-targeted drugs have been successfully marketed, which urgently requires more strategies. Heat shock proteins (HSPs), especially Hsp90 and Hsp70, have been found to play a crucial role in Tau maturation and degradation. This review explores innovative approaches using small molecules that interact with the chaperone system to regulate Tau levels. We provide a comprehensive overview of the mechanisms involving HSPs and their co-chaperones in the Tau regulation cycle. Additionally, we analyze small molecules targeting these chaperone systems to modulate Tau function. By understanding the characteristics of the molecular chaperone system and its specific impact on Tau, we aim to provide a perspective that seeks to regulate Tau levels through the manipulation of the molecular chaperone system and ultimately develop effective treatments for AD.