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.

  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alzheimer's disease (AD) belongs to a group of neurodegenerative diseases collectively designated as "tauopathies", because they are characterized by the aggregation of abnormally phosphorylated tau protein. The mechanisms responsible for tau aggregation and its contribution to neurodegeneration are still unknown. Thereby, understanding the modes of regulation of tau is of high interest in the determination of the possible causes at the origin of the formation of tau aggregates and to elaborate protection strategies to cope with these pathological lesions. The regulation of tau takes place predominantly through post-translational modifications. Extensive reports have been published about tau phosphorylation; however, the other tau post-translational modifications have received much less attention. Here, we review the different types of post-translational modifications of tau including phosphorylation, glycosylation, glycation, prolyl-isomerization, cleavage or truncation, nitration, polyamination, ubiquitination, sumoylation, oxidation and aggregation, with a particular interest towards their relevance in AD.
    Neurochemistry International 03/2011; 58(4):458-71. DOI:10.1016/j.neuint.2010.12.023 · 2.65 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Progressive supranuclear palsy is a sporadic and progressive neurodegenerative disease, most often presenting as a symmetric, akinetic-rigid syndrome with postural instability, vertical supranuclear gaze palsy and frontal lobe deficits. It belongs to the family of tauopathies and involves both cortical and subcortical structures. Although the exact pathophysiology is not yet fully understood, several lines of evidence point to a crucial contribution from both genetic predisposition and mitochondrial dysfunction. Recently gained insights into the pathophysiology of this disease have led to several hypothesis-driven therapeutic approaches aiming at disease-modification rather than mere symptomatic neurotransmitter-replacement therapy. Agents targeting mitochondrial dysfunction have already shown a positive effect in a phase II study and further studies to verify and expand these results are ongoing. Clinical studies with agents targeting tau dysfunction such as tau-kinase inhibitors, tau-aggregation inhibitors and microtubule stabilizers are in preparation or ongoing. This review presents the current pathophysiological concepts driving these exciting therapeutic developments.
    Brain 06/2010; 133(Pt 6):1578-90. DOI:10.1093/brain/awq115 · 10.23 Impact Factor
Show more