Hsp70 ATPase Modulators as Therapeutics for Alzheimer's and other Neurodegenerative Diseases

Abstract

Neurodegenerative diseases caused by abnormal accumulation of the microtubule associated protein tau (MAPT, tau) are collectively called tauopathies. The most devastating tau related disorder is Alzheimer's disease (AD). Molecular chaperones such as heat shock proteins (Hsp) have emerged as critical regulators of tau stability. Several studies from our group and others have shown that the chaperone network can be targeted for the development of therapeutic strategies for AD and other neurodegenerative diseases. Here we will discuss a recent paper and current work from our laboratory where we have manipulated the ATPase activity of the 70-kDa heat shock protein (Hsp70) to regulate tau turnover. A high-throughput screening assay revealed several compounds that activated or inhibited Hsp70's ATPase activity. Inhibitors dramatically and rapidly reduced tau levels, whereas activators stabilized tau, both in cells and brain tissue. Moreover, increased levels of Hsp70 improved ATPase inhibitor efficacy, suggesting that therapies aimed at inducing Hsp70 levels followed by inhibition of its ATPase activity may be a very effective strategy to treat AD. These findings demonstrate that Hsp70 ATPase activity can be targeted to modify the pathologies of AD and other tauopathies.

Figure 1. Inhibition of Hsp70 ATPase activity reduces tau in the neuron

Primary neurons were obtained from mouse brain and treated with various doses of Hsp70 ATPase inhibitor MB or vehicle DMSO control for 1 hour. Western blot analysis of samples showed a dose dependent reduction in tau.

Figure 2. Increasing Hsp70 levels enhances the Hsp70 activator drug efficacy

HeLa cells stably overexpressing wild type human 4R tau were co-transfected with vector or myc-tagged Hsp70 and cells were treated with the indicated dose of ATPase activator (SW02) for 24 hours. Analysis by western blotting showed that overexpression of Hsp70 dramatically enhances the effectiveness of SW02.

Figure 3. Schematic model showing distinctions between Hsp70 and Hsp90 inhibition with regard to tau biology

Tau recognized by the chaperone system is processed initially by the Hsp70/Hsp40 complex and then forms an intermediate complex with Hsp90 and HOP. Inhibitors designed to target Hsp70 (blue hexagons) bypass the intermediate complex formation step and facilitate immediate tau degradation via the proteasome. Inhibitors designed to target Hsp90 (green hexagons) require Hsp70 to facilitate the intermediate complex formation and then Hsp90 inhibitors can promote tau degradation. Another important distinction between these two inhibitors is that Hsp70 inhibitors have no effect on HSF1 activation, while Hsp90 inhibitors promote HSF1 activity.