Abisambra J, Jinwal UK, Miyata Y, Rogers J, Blair L, Li X, Seguin SP, Wang L, Jin Y, Bacon J, Brady S, Cockman M, Guidi C, Zhang J, Koren J, Young ZT, Atkins CA, Zhang B, Lawson LY, Weeber EJ, Brodsky JL, Gestwicki JE, Dickey CA.
Allosteric Heat Shock Protein 70 Inhibitors Rapidly Rescue Synaptic Plasticity Deficits by Reducing Aberrant Tau.
Biol Psychiatry. 2013 Apr 19;
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This exciting work from Abisambra and colleagues reports that synaptic plasticity deficits in AD can be rescued with heat shock protein 70 inhibitors, which function to reduce abnormal pools of tau. While previous work has identified Hsp70 as a regulator of tau homeostasis and posited it as a reasonable therapeutic target in AD (Patterson et al., 2011; Pettrucelli et., al., 2004), this investigation instead focuses on Hsc70, the constitutively expressed form of Hsp70, which can actually slow tau clearance and facilitate its pathogenicity (Jinwal et al., 2010). In this work, the authors report that the Hsc70-binding compound YM-01 rapidly and potently reduces tau levels in cell lines and in brain slice cultures derived from transgenic tauopathy mice. Importantly, this molecule does not affect tau levels in wild-type brain slices unless microtubules are destabilized, which artificially increases the amount of aberrant free tau. This result, therefore, suggests that YM-01 is selective for pathogenic tau. Since a proteasome inhibitor blocks the YM-01-mediated tau reduction in both cell lines and brain slices, it can be assumed that YM-01 facilitates the normal triage functions of Hsc70, which include shuttling aberrant tau to the proteasome for degradation. Finally, using hippocampal slices from both controls and rTg4510 tauopathy mice, which develop LTP deficits very early on, the authors demonstrated that YM-01 rescues synaptic plasticity defects.
This is an interesting study that utilizes the exquisite nature of the Hsp70 chaperone protein family, which is capable of distinguishing between functional and pathogenic-free tau. The importance of selectively reducing pathologic tau while not impacting functional tau levels is clear, as a complete loss of tau could have toxic consequences. The results demonstrated here are consistent with prior studies demonstrating a reduction in hyperphosphorylated and aggregated tau as well as a rescue of learning deficits in transgenic tauopathy mouse models using the Hsp70 inhibitor methylene blue (O'Leary et al., 2010; Congdon et al., 2012). However, methylene blue lacks adequate selectivity. It tends to distribute in the liver when given orally, and its long-term use in rodents leads to lymphomas and intestinal malignancies (Oz et al., 2009).
YM-01 is an analog of another anti-cancer agent, MKT-077, which has been shown to stabilize the ADP-bound form of Hsc70 through allosteric binding (Rousaki et al., 2011). As more potent and more selective inhibitors than methylene blue, these agents show therapeutic potential. However, a phase I clinical trial for cancer revealed that MKT-077 causes nephrotoxicity (Propper et al., 1999). Encouragingly, the MKT-077 derivative YM-01 demonstrated greater toxicity in cancer cells, possibly due to its primary localization within the cytosol rather than the mitochondria. This altered cellular localization is also thought to lead to lower renal toxicity. The minor changes between these compounds will hopefully enable YM-01 to be a more effective and less toxic drug candidate, both for preventing refractory cancer cells from developing tamoxifen resistance, as well as for facilitating tau clearance in tauopathies.
Finally, this study has particular relevance since YM-01 targets synaptic deficits. While the extent and location of tau pathology in AD closely follows the spatial and temporal clinical course of the disease (unlike amyloid plaque deposition), the most robust correlate with AD clinical progression is the degree of synapse loss (Davis, 1987; Masliah et. al 2001; Scheff et al., 2007). Since functional rescue of synaptic transmission and improved learning and memory are ultimate goals for AD therapeutics, YM-01 holds substantial promise as an effective treatment strategy.
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