AbstractBackgroundAlzheimer disease (AD) is a complex multifactorial disease representing >60 % cases of dementia with no disease modifying therapies available in clinics largely due to its poorly understood pathology. One of the new proteins that recently emerged as a promising target in AD therapy is FKBP51, or FK506‐binding protein 51 kDa. FKBP51, together with its partner, a molecular chaperone heat shock protein 90 kDa (Hsp90), have been found to play an important role in metabolism of tau promoting its accumulation and aggregation. In vitro, in vivo and epidemiological studies also suggest an important role of FKBP51 in control of body weight and insulin resistance.MethodRecently, we have successfully obtained several active compounds able to inhibit FKBP51‐Hsp90 interactions both in in vitro assays and in human cell lines. SH‐SY5Y cells, differentiated human adipocytes were treated with FKBP51‐Hsp90 interaction inhibitors. Effect of compounds on energy metabolism, lipid metabolism as well on tau accumulation was analyzed. Using RNAseq we have analyzed transcriptome changes upon compound treatment.ResultAddition of compounds resulted in profound stimulation of energy metabolism both in SH‐SY5Y cells and differentiated adipocytes. Significant increase in mitochondrial membrane potential was also observed. Dramatic decrease in size and number of lipid droplets was observed in differentiated adipocytes upon compound treatment. RNAseq results show increased expression of genes involved in lipid catabolism, beta‐oxidation and thermogenesis. We have also observed decreased tau levels in the treated SH‐SY5Y cells.ConclusionOur data implicate FKBP51 as a possible target for AD treatment affecting cell energy metabolism and tau accumulation.