Further understanding of tau phosphorylation: implications for therapy

Abstract

Tau is a brain microtubule-associated protein that regulates microtubule structure and function. Prominent tau neurofibrillary pathology is a common feature in a number of neurodegenerative disorders collectively referred to as tauopathies, the most common of which is Alzheimer’s disease. Beyond its classical role as a microtubule-associated protein, recent advances in our understanding of tau cellular functions have unveiled novel important tau cellular functions that may also play a pivotal role in pathogenesis and render novel targets for therapeutic intervention. Regulation of tau behavior and function under physiological and pathological conditions is mainly achieved through post-translational modifications, especially phosphorylation, which has significant implications for the development of novel therapeutic approaches in a number of neurodegenerative disorders.

Keywords:

• aggregation
• Alzheimer
• dementia
• kinases
• memory
• neurodegeneration
• neurofibrillary tangles
• phosphorylation
• tau
• tauopathies

Financial & competing interests disclosure

The authors would like to thank Spanish Plan Nacional, CIBERNED, Queen Sofia Foundation and Comunidad de Madrid for financial support. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Tau hyperphosphorylation is a common feature in a group of neurodegenerative disorders collectively known as tauopathies, including Alzheimer’s disease (AD).

• Tau binding to microtubules and most, if not any, other tau cellular functions are regulated by phosphorylation and its phosphorylation state is developmentally regulated.

• Tau protein has up to 85 potential phosphorylation sites, mostly Ser and Thr residues.

• While normal adult brain tau is estimated to contains 2–3 moles of phosphate per mole of the protein, tau protein from AD brains has up to 8–10 phosphate moles per mole of protein.

• There is not a single but multiple kinases involved in phosphorylating tau in vivo. Glycogen synthase kinase-3 inhibitors are the only agents directly targeting tau phosphorylation that have reached Phase II clinical trials for AD and progressive supranuclear palsy.

• Phosphorylation may also play a key role in cell-to-cell spreading of tau pathology.

• Phosphorylation at different sites has different consequences for tau function.

• Inhibition of phosphorylation is a promising therapeutic strategy for the treatment of AD and other tauopathies.