Neurodegenerative disease in 2015: Targeting tauopathies for therapeutic translation

Abstract

Tau protein abnormalities are key pathogenic components of Alzheimer disease and other neurodegenerative diseases. New studies in the less common primary tauopathies, including progressive supranuclear palsy, chronic traumatic encephalopathy and frontotemporal lobar degeneration have identified novel mechanisms that initiate tau pathology and biomarkers to measure disease during life.

Figure 1. Advances in tau research in 2015

The rs1768208 polymorphism, linked with progressive supranuclear palsy (PSP), elevates the level of appoptosin, thereby promoting caspase-3-mediated tau cleavage. It is hypothesized that in both PSP and Alzheimer disease (AD), the cleaved tau spreads transsynaptically, causing disease. The tau-associated neuropathology can be detected with tau-sensitive PET. One of the main functions of tau protein, encoded by the MAPT gene, is to stabilize microtubules. MAPT H1/H1 haplotype is associated with PSP, and MRI can reveal brain atrophy in asymptomatic MAPT mutation carriers. PIN1 polymorphisms promote formation of toxic cis-p-tau. Traumatic brain injury (TBI) induces cis-p-tau formation that leads to neuronal dysfunction in animal models. In patients with TBI, blood levels of tau are elevated.