Therapeutic strategies for the treatment of tauopathies: Hopes and challenges

Abstract

A group of neurodegenerative diseases referred to as tauopathies are characterized by the presence of brain cells harboring inclusions of pathological species of the tau protein. These disorders include Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) due to tau pathology, including progressive supranuclear palsy, corticobasal degeneration and Pick’s disease. Tau is normally a microtubule-associated protein that appears to play an important role in ensuring proper axonal transport, but in tauopathies tau becomes hyperphosphorylated and disengages from microtubules, with consequent misfolding and deposition into inclusions that mainly affect neurons, but also glia. A body of experimental evidence suggests that the development of tau inclusions leads to the neurodegeneration observed in tauopathies, and there is a growing interest in developing tau-directed therapeutic agents. The following review provides a summary of strategies under investigation for the potential treatment of tauopathies, highlighting both the promises and challenges associated with these various therapeutic approaches.

Advances in progressive supranuclear palsy: new diagnostic criteria, biomarkers, and therapeutic approaches

“…Two general types of tau dysfunction are thought to lead to disease: loss of normal tau function or toxic gain of tau function. 69 These mechanisms are not mutually exclusive, and it is possible that toxic gain of function in one cellular compartment might lead to loss of tau function in others.…”

“…69 A number of microtubule-stabilizing agents have been developed and three have been explored in human neurodegenerative disease clinical trials. Davunetide is a microtubule stabilizing octapeptide that demonstrated benefits in animal models of tauopathy.…”

A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies

“…Therapeutic efforts focused on targeting any one of the aforementioned features of pathogenic tau have been recently reviewed [20], and include but are not limited to inhibitors of aberrant tau post-translational modifications, proteolytic processing, and aggregation. A strategy utilizing antisense oligonucleotides to reduce tau mRNA has recently been reported to decrease pathogenic tau, halt neuronal loss, and extend lifespan of mice transgenically expressing human tau harboring the disease-associated P301S mutation (PS19 mouse model), even when administered well after tau deposition [21].…”

Altered microtubule dynamics in neurodegenerative disease: Therapeutic potential of microtubule-stabilizing drugs

“…In addition, most AD cases also have α-synuclein and TDP-43 inclusions (Irwin et al, 2013; Nelson et al, 2016), so AD is most commonly a mixed proteinopathy, and cerebrovascular pathology is also common in AD (Toledo et al, 2013). Although the Aβ pathology observed in AD has historically been the major focus of pharmaceutical efforts for the treatment of AD, based largely on familial mutations that clearly implicate the Aβ peptide in AD (George-Hyslop and Petit, 2005), the repeated clinical failures of Aβ-directed drugs has led to a growing interest in tau-directed therapeutic strategies (Khanna et al, 2016). As noted above, tau is believed to play a critical role in MT structure and function, and the hyperphosphorylation and deposition of tau into inclusions in the various tauopathies is believed to lead to the neuronal dysfunction and death observed in these diseases.…”