Potential synergy between tau aggregation inhibitors and tau chaperonemodulators

Tau is a soluble, microtubule-associated protein known to aberrantly formamyloid-positive aggregates. This pathology is characteristic for more than 15neuropathies, the most common of which is Alzheimer’s disease. Findingtherapeutics to reverse or remove this non-native tau state is of greatinterest; however, at this time only one drug is entering phase III clinicaltrials for treating tauopathies. Generally, tau manipulation by therapeutics caneither directly or indirectly alter tau aggregation and stability. Drugs thatbind and change the conformation of tau itself are largely classified asaggregation inhibitors, while drugs that alter the activity of a tau-effectorprotein fall into several categories, such as kinase inhibitors, microtubulestabilizers, or chaperone modulators. Chaperone inhibitors that have proveneffective in tau models include heat shock protein 90 inhibitors, heat shockprotein 70 inhibitors and activators, as well as inducers of heat shockproteins. While many of these compounds can alter tau levels and/or aggregationstates, it is possible that combining these approaches may produce the mostoptimal outcome. However, because many of these compounds have multipleoff-target effects or poor blood–brain barrier permeability, thedevelopment of this synergistic therapeutic strategy presents significantchallenges. This review will summarize many of the drugs that have beenidentified to alter tau biology, with special focus on therapeutics that preventtau aggregation and regulate chaperone-mediated clearance of tau.