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


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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Available from: Boris Schmidt, Oct 04, 2015
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    • "Brain cell apoptosis inhibitor: Dimebon: Phase II completed. Operates through multiple mechanisms: Blocks the action of neurotoxic beta-amyloid proteins and inhibits L-type calcium channels, [31] modulates the action of AMPA and NMDA glutamate receptors,[32] may exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores,[33] and blocks a number of other receptors, including α-adrenergic, 5-HT 2C , 5-HT 5A , and 5-HT 6 [34] 4.3.2: Nootropic drugs like Piribedil,a dopaminergic agonist; Citicoline, a compound derived from choline and cytidine and Dihydroergotamine, α adrenergic blocking : improve memory, behaviour, concentration and vigilance. "
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    • "Tau contains a well-characterized, aggregation-prone peptide sequence in the third microtubule binding repeat domain of exon 10+ tau. This hexapeptide motif, VQIVYK, located at amino acids 306 to 311, has been shown to exhibit the highest propensity to aggregate [8]. Drugs that directly bind near this hexapeptide region have been the most effective at preventing tau aggregation [9]. "
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    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.
    Alzheimer's Research and Therapy 09/2013; 5(5):41. DOI:10.1186/alzrt207 · 3.98 Impact Factor
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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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    ABSTRACT: Alzheimer's disease is a neurodegenerative disorder involving extracellular plaques (amyloid-β) and intracellular tangles of tau protein. Recently, tangle formation has been identified as a major event involved in the neurodegenerative process, due to the conversion of either soluble peptides or oligomers into insoluble filaments. At present, the current therapeutic strategies are aimed at natural phytocomplexes and polyphenolics compounds able to either inhibit the formation of tau filaments or disaggregate them. However, only a few polyphenolic molecules have emerged to prevent tau aggregation, and natural drugs targeting tau have not been approved yet. Fulvic acid, a humic substance, has several nutraceutical properties with potential activity to protect cognitive impairment. In this work we provide evidence to show that the aggregation process of tau protein, forming paired helical filaments (PHFs) in vitro, is inhibited by fulvic acid affecting the length of fibrils and their morphology. In addition, we investigated whether fulvic acid is capable of disassembling preformed PHFs. We show that the fulvic acid is an active compound against preformed fibrils affecting the whole structure by diminishing length of PHFs and probably acting at the hydrophobic level, as we observed by atomic force techniques. Thus, fulvic acid is likely to provide new insights in the development of potential treatments for Alzheimer's disease using natural products.
    Journal of Alzheimer's disease: JAD 07/2011; 27(1):143-53. DOI:10.3233/JAD-2011-110623 · 4.15 Impact Factor
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