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.
Keywords: Alzheimer’s disease, Anti-tau therapy, Microtubules, Mitochondrial
dysfunction, Tauopathies, Tau protein.
