Tau-Targeted Therapy in Alzheimer's Disease - History and Current State

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The two main histopathological hallmarks still required for the diagnosis of Alzheimer's disease are the presence of amyloid plaques and intraneuronal neurofibrillary tangles formed mainly of tau protein. Normally, tau protein regulates intracellular trafficking and provides microtubule stability. However, in AD as well as in other tauopathies, there is a disruption in the normal function of tau, leading to the development of neurofibrillary tangles with disease-dependent ultrastructure of the tau filaments. After several failures of trials with drugs trying to prevent the accumulation of amyloid, tau protein became another target of molecules designed to modify the course of AD. Each stage in the development of tau pathology, from the expression of tau protein to its post-translational modifications, with the protein’s aggregation and impaired clearance, presents opportunities for therapeutic intervention: reducing tau expression with antisense oligonucleotides, reducing tau phosphorylation with kinase inhibitors, inhibiting tau acetylation, tau deglycosylation, tau aggregation, modulating tau degradation, stabilizing the microtubules, as well as active or passive anti-tau immunotherapies (with various monoclonal antibodies), have been attempted or are still in trials, with rather inconclusive results so far. It appears that an efficient diseasemodifying therapy is not yet available. Given the complex pathophysiology of Alzheimer’s disease, most likely, a multi-targeted approach would be more effective.