Abstract Body

Recent years, several clinical trials on Alzheimer disease (AD) targeting beta amyloid or tau via active or passive immunization have been completed. So far, one treatment (aducanumab from Biogen) has received FDA approval. To make drug treatment available for the great number of persons diagnosed with AD, there is a need for an effective, easily administered (oral) and reasonably costly drug. Therefore, we need to continue developing small molecules able to slow down AD progression.

AD is a multifactorial disease where beta amyloid and tau accumulation in the brain accompanied with oxidative stress, metabolic dysfunction such as decreased glucose utilization and brain insulin resistance (IR), progressive synaptic loss and increased neuroinflammation. Simultaneous targeting of several key pathologies with small molecules holds a promise to slow down AD progression.

FKBP51, FK506-binding protein 51 kDa, recently emerged as a possible AD therapeutic target for resolving tau aggregation and IR. Together with its binding partner molecular chaperone Hsp90, FKBP51 preserves toxic tau linked to AD pathogenesis. Also, studies suggest an important role for FKBP51 in controlling IR. The link between tau aggregation and cerebral IR in AD suggests a novel therapeutic concept based on regulating FKBP51 function by inhibiting its interaction with Hsp90 using small molecules.

We have recently developed small molecules inhibiting FKBP51-Hsp90 interactions. Using these novel pharmacological tools, we are investigating their effect in various cell-based and in vivo models of tauopathy and IR. If successful, our results will open new avenues for the therapy of AD.