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Review
. 2013 Sep 16;5(5):41.
doi: 10.1186/alzrt207. eCollection 2013.

Potential synergy between tau aggregation inhibitors and tau chaperone modulators

Laura J Blair  1 , Bo Zhang  1 , Chad A Dickey  1
Affiliations
Review

Potential synergy between tau aggregation inhibitors and tau chaperone modulators

Laura J Blair et al. Alzheimers Res Ther. .

Abstract

Tau is a soluble, microtubule-associated protein known to aberrantly form amyloid-positive aggregates. This pathology is characteristic for more than 15 neuropathies, the most common of which is Alzheimer's disease. Finding therapeutics to reverse or remove this non-native tau state is of great interest; however, at this time only one drug is entering phase III clinical trials for treating tauopathies. Generally, tau manipulation by therapeutics can either directly or indirectly alter tau aggregation and stability. Drugs that bind and change the conformation of tau itself are largely classified as aggregation inhibitors, while drugs that alter the activity of a tau-effector protein fall into several categories, such as kinase inhibitors, microtubule stabilizers, or chaperone modulators. Chaperone inhibitors that have proven effective in tau models include heat shock protein 90 inhibitors, heat shock protein 70 inhibitors and activators, as well as inducers of heat shock proteins. While many of these compounds can alter tau levels and/or aggregation states, it is possible that combining these approaches may produce the most optimal outcome. However, because many of these compounds have multiple off-target effects or poor blood-brain barrier permeability, the development of this synergistic therapeutic strategy presents significant challenges. This review will summarize many of the drugs that have been identified to alter tau biology, with special focus on therapeutics that prevent tau aggregation and regulate chaperone-mediated clearance of tau.

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References

    1. Hardy J, Orr H. The genetics of neurodegenerative diseases. J Neurochem. 2006;5:1690–1699. doi: 10.1111/j.1471-4159.2006.03979.x. - DOI - PubMed
    1. Abisambra JF, Blair LJ, Hill SE, Jones J, Kraft C, Rogers J, Koren J, Jinwal UK, Lawson LY, Johnson AG, Wilcock D, O'Leary JC, Jansen-West K, Muschol M, Golde TE, Weeber EJ, Banko J, Dickey CA. Phosphorylation dynamics regulate Hsp27-mediated rescue of neuronal plasticity deficits in tau transgenic mice. J Neurosci. 2010;5:15374–15382. doi: 10.1523/JNEUROSCI.3155-10.2010. - DOI - PMC - PubMed
    1. Voss K, Combs B, Patterson KR, Binder LI, Gamblin TC. Hsp70 alters tau function and aggregation in an isoform specific manner. Biochemistry. 2012;5:888–898. doi: 10.1021/bi2018078. - DOI - PMC - PubMed
    1. Thompson AD, Scaglione KM, Prensner J, Gillies AT, Chinnaiyan A, Paulson HL, Jinwal UK, Dickey CA, Gestwicki JE. Analysis of the tau-associated proteome reveals that exchange of Hsp70 for Hsp90 is involved in tau degradation. ACS Chem Biol. 2012;5:1677–1686. doi: 10.1021/cb3002599. - DOI - PMC - PubMed
    1. Daccache A, Lion C, Sibille N, Gerard M, Slomianny C, Lippens G, Cotelle P. Oleuropein and derivatives from olives as Tau aggregation inhibitors. Neurochem Int. 2011;5:700–707. doi: 10.1016/j.neuint.2011.02.010. - DOI - PubMed