Tau as a therapeutic target in neurodegenerative disease

Abstract

Tau is a microtubule-associated protein thought to help modulate the stability of neuronal microtubules. In tauopathies, including Alzheimer’s disease and several frontotemporal dementias, tau is abnormally modified and misfolded resulting in its disassociation from microtubules and the generation of pathological lesions characteristic for each disease. A recent surge in the population of people with neurodegenerative tauopathies has highlighted the immense need for disease-modifying therapies for these conditions, and new attention has focused on tau as a potential target for intervention. In the current work we summarize evidence linking tau to disease pathogenesis and review recent therapeutic approaches aimed at ameliorating tau dysfunction. The primary therapeutic tactics considered include kinase inhibitors and phosphatase activators, immunotherapies, small molecule inhibitors of protein aggregation, and microtubule-stabilizing agents. Although the evidence for tau-based treatments is encouraging, additional work is undoubtedly needed to optimize each treatment strategy for the successful development of safe and effective therapeutics.

Innate Immune System and Inflammation in Alzheimer's Disease: From Pathogenesis to Treatment

“…Tau phosphorylation leads to its dissociation from microtubules within the cells and to the formation of neurotoxic neurotrophic factors. Aβ immunotherapy results in a very limited indirect clearance of tau aggregates in dystrophic neuritis, showing the importance of developing parallel and specific immunotherapeutic approaches directed against pathological tau protein [67]. Vaccination approaches have been considered, but the development of a successful therapy is complicated by the fact that tau protein is intracellular.…”

The α-Tubulin Deacetylase HDAC6 in Aggresome Formation and Autophagy

“…Its microtubule binding activity is regulated by post-translational modification, mainly by phosphorylation. However, other modifications have been reported, including glycation, ubiquitylation, sumoylation, and acetylation (Himmelstein et al, 2012). HDAC6 interacts with the microtubule binding domain of tau via its SE14-region ( Figure 18.1).…”

Protein aggregate formation in oligodendrocytes: tau and the cytoskeleton at the intersection of neuroprotection and neurodegeneration

“…Its MT-binding activity is regulated by posttranslational modifications, mainly by phosphorylation, but also glycation, ubiquitylation, sumoylation and acetylation have been reported (Himmelstein et al, 2012). Tau can be phosphorylated by many kinases and becomes hyperphosphorylated in AD and other tauopathies.…”