FKBP51‐Hsp90 complex as a novel therapeutic target for Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is the most common form of dementia without effective treatments. FK506‐binding protein 51 (FKBP51) recently emerged as a possible therapeutic target for resolving both tau aggregation and insulin resistance in AD. FKBP51 in complex with its partner, molecular chaperone Hsp90, increases tau stability, thereby promoting tau aggregation [1, 2]. FKBP51 also regulates insulin resistance and altered glucose metabolism which represent early events that precede or accompany the development of AD [3, 4]. Our study aims to investigate the potential roles of FKBP51‐Hsp90 interaction inhibitors in AD.MethodsA large dataset of available compounds were investigated using AlphaScreen™ and in silico virtual screening techniques to evaluate their inhibition on FKBP51‐Hsp90 interactions. Two of the selected specific inhibitors, E8 and C674, were then applied to SH‐SY5Y cells to test their effects on neurite outgrowth, overexpressed tau levels and glucose uptake. Furthermore, insulin signaling pathways were compared between vehicle‐treated vs inhibitor‐treated AD specimens.ResultsCompounds E8 and C674 inhibit FKBP51‐Hsp90 interactions at sub‐micromolar concentrations. E8 and C674 enhance neurite elongation, reduce overexpressed tau levels, stimulate glucose uptake and regulate insulin resistance.ConclusionWe showed that inhibiting specific FKBP51‐Hsp90 interactions with small molecules provides novel therapeutic targets for AD.