Hsp90 Inhibition for Treatment of Alzheimer’s disease and tauopathies

Therapeutic development for Alzheimer’s disease (AD) has largely focused on the removal of beta amyloid because of its suggested role as the primary agent in initiating the disease process. However, with the recent discovery of mutations that result in pathologic buildup of tau in the absence of amyloid pathology, tau is beginning to be recognized as a potential target for drug discovery. Perhaps the first potential point of intervention would be at the initial protein misfolding stage. Molecular chaperones can both refold misfolded proteins and/or target them for proteasomal degradation. The heat shock response can increase levels of protein chaperones. Hsp90 inhibitors such as geldanamycin and its derivatives can pharmacologically modulate chaperone levels. We have developed a high-throughput drug screening method that allows for direct intracellular quantitation of native and aberrant tau protein species, enabling the fast, reliable detection of these changes. We have identified a family of small, blood brain barrier penetrant heat shock protein 90 inhibitors that significantly reduce abnormal tau protein levels in vitro. On going studies in the laboratory will determine if elevation of heat shock proteins (HSPs) may delay the progression of disease in mouse models of tauopathy.