The role of the FKBP51-Hsp90 complex in Alzheimer's disease: An emerging new drug target.

With increasing age comes the inevitable decline in proteostasis, where chaperone and co-chaperone activity becomes imbalanced. These changes lead to global disturbances and pathogenic rewiring of the chaperone system into epichaperones consisting of protein networks that are ultimately dysfunctional. Such imbalances in proteostasis may favor mechanisms that can lead to neurological diseases, such as Alzheimer's disease (AD). Consequently, there has been an increase in research activity toward finding small molecules that can re-balance the chaperone and co-chaperone machinery to counter the effects of disease resulting from old age. The Hsp90 co-chaperone FKBP51 has recently been identified as a protein whose induction not only increases with age but is elevated further in AD cells. Significantly, FKBP51 plays a role in the Hsp90-dependent isomerization of tau, which in turn influences its phosphorylation and susceptibility to aggregation. We hypothesize that FKBP51 is a major player that is able to elicit tauopathy in response to amyloid-beta senile plaques that damage the brain. We propose that elevated FKBP51 levels result in an abnormal FKBP51-Hsp90 activity that alters the normal processing of tau, which manifests as hyperphosphorylation and oligomerization of tau. Thus, the Hsp90-FKBP51 complex is emerging as a drug target against AD. In support of this idea, the structure of the FKBP51-Hsp90 complex was recently described, and significantly, the small-molecule dihydropyridine LA1011 was shown to be able to disrupt the Hsp90-FKBP51 complex. LA1011 was previously shown to effectively prevent neurodegeneration in the APPxPS1 AD transgenic mouse model. This review looks at the role of Hsp90 and its co-chaperones in AD with a focus on FKBP51.