Article

Development of Tau Aggregation Inhibitors for Alzheimer's Disease

Max-Planck-Institute for Molecular Physiology, Dortmund, Germany.
Angewandte Chemie International Edition (Impact Factor: 11.26). 02/2009; 48(10):1740-52. DOI: 10.1002/anie.200802621
Source: PubMed

ABSTRACT A variety of human diseases are suspected to be directly linked to protein misfolding. Highly organized protein aggregates, called amyloid fibrils, and aggregation intermediates are observed; these are considered to be mediators of cellular toxicity and thus attract a great deal of attention from investigators. Neurodegenerative pathologies such as Alzheimer's disease account for a major part of these protein misfolding diseases. The last decade has witnessed a renaissance of interest in inhibitors of tau aggregation as potential disease-modifying drugs for Alzheimer's disease and other "tauopathies". The recent report of a phase II clinical trial with the tau aggregation inhibitor MTC could hold promise for the validation of the concept. This Review summarizes the available data concerning small-molecule inhibitors of tau aggregation from a medicinal chemistry point of view.

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    • "In this context, it seems timely to consider alternative drug discovery strategies for AD based on approaches directed at reducing misfolded tau and compensating for the loss of normal tau function [12]. Therefore, the development of small molecules that inhibit the aggregation of tau appears to be a valid therapeutic target for treatment of AD and other tauopathies [13]. This hypothesis has been favored by current findings on the compound methylthioninium chloride (MTC, also known as methylene blue), a previously described inhibitor of the aggregation of tau of the phenothiazine's family [14] [15]. "
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    • "PHFs isolated from AD brains or hyperphosphorylated tau have been demonstrated to block degradation by UPS and to disrupt cellular homeostasis (Keck et al., 2003; Ren et al., 2007). This suggests that PHFs are an integral part of cellular regulation and are important mediators of cell toxicity that lead to AD (Bulic et al., 2009). "
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    • "Substances activating tau-phosphatases (Le Corre et al., 2006) may also be of therapeutic interest. There is also experimental evidence in vivo and in vitro suggesting a therapeutic benefit from small molecules acting as tau-aggregation inhibitors (Fig. 4C; for review see Bulic et al., 2009). Recently, methylthioninium chloride was orally administered for 84 weeks in a double-blind, randomized phase II trial to 321 participants with Alzheimer's disease, which has tau-pathology similar to PSP. "
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