Chapter 11: Rationale for Tau-Aggregation Inhibitor Therapy in Alzheimer's Disease and Other Tauopathies
Published:07 May 2010
C. M. Wischik, D. J. Wischik, J. M. Storey, and C. R. Harrington, in Emerging Drugs and Targets for Alzheimer's Disease: Volume 1: Beta-Amyloid, Tau Protein and Glucose Metabolism, ed. A. Martinez and A. Martinez, The Royal Society of Chemistry, 2010, vol. 1, ch. 11, pp. 210-232.
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Alzheimer's disease is an irreversible, neurodegenerative disorder characterized by the progressive loss of memory and thinking skills. A close correlate of this cognitive decline is the aggregation of tau protein, of which neurofibrillary tangles are composed. The process of tau aggregation follows a stereotypical pattern of spread throughout the cortex which begins well before the tangles appear. Autocatalytic capture and assembly of tau into oligomeric aggregates and subsequently into filaments has been replicated in cellular and transgenic models of tau aggregation. It is postulated that in sporadic AD, an age-related defect in mitochondrial turnover producing congestion in the endosomal-lysosomal pathway leads both to nucleation of tau aggregation and decreased capacity of this pathway to clear tau oligomers which are free to propagate further tau aggregation. Upstream intervention aiming to reduce tau entry into the autocatalytic aggregation pathway is predicted to have a purely transient effect. By contrast, disaggregation of oligomers offers the potential to alter the rate of disease progression by facilitating clearance of the constituent monomers through the more efficient proteasomal pathway and bypassing the endosomal-lysosomal pathway. This forms the basis of the rationale for using methylthioninium chloride (MTC) as the first Tau Aggregation Inhibitor, or TAI. MTC has proven effective in reversing both cognitive deficits and tau pathology in transgenic mice. In a phase 2 clinical trial of 321 subjects with mild or moderate AD, MTC reduced the rate of disease progression by 84% over 50 weeks when measured by the ADAS-cog scale.