The novel FKBP51‐Hsp90 interaction inhibitor attenuates high‐fat diet induced cognitive impairment

Obesity increases the risk of several chronic diseases, such as type 2 diabetes mellitus, insulin resistance, and Alzheimer disease. As one of the co‐chaperones of heat shock protein 90 (Hsp90), FK506‐binding protein 51 (FKBP51) is an important regulator of metabolic and cognitive dysfunction. FKBP51 knockout mice are resistant to diet‐induced obesity, exhibit elevated glucose and insulin tolerance and have less endogenous tau. FKBP51 overexpression preserves tau and impairs spatial reversal learning and memory. Our group has identified a new family of FKBP51 inhibitors that can disrupt FKBP51‐Hsp90 interactions. Previous study has shown that our inhibitors can dose‐dependently reduce lipid accumulation in adipocytes differentiated from primary human mesenchymal stem cells and stimulate neurite outgrowth in differentiated neuroblastoma SH‐SY5Y cells. This study aims to investigate the potential roles of our inhibitors on metabolic and cognitive dysfunction in vivo.