Tau in neurodegenerative disease

Abstract

Tau, a microtubule-associated protein, is the main component of the intracellular filamentous inclusions that are involved in neurodegenerative diseases known as tauopathies, including Alzheimer disease (AD), frontotemporal dementia with parkinsonism-17 (FTDP-17), Pick disease (PiD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Hyperphosphorylated, aggregated tau proteins form the core of neurofibrillary tangles (NFTs), which are shown to be one of the pathological hallmarks of AD. The discovery of mutations in the microtubule-associated protein tau (MAPT) gene in patients with FTDP-17 also contributes to a better understanding of the dysfunctional tau as a cause of diseases. Although recent substantial progress has been made in the tau pathology of tauopathies, the mechanisms underlying tau-induced neurodegeneration remain unclear. Here, we present an overview of the biochemical properties of tau protein and the pathogenesis underlying tau-induced neurodegenerative diseases. Meanwhile, we will discuss the tau-related biomarkers and ongoing tau-targeted strategies for therapeutic modulation.

Keywords: Tau protein; biomarkers; mechanisms; neurodegenerative diseases; therapeutic.

Figure 1

Tau gene and six isoforms in the human brain. (A) Tau gene, MAPT, comprises 16 exons (E). N1 and N2 is encoded by E2 (green) and E3 (purple), respectively. The repeat R2 is encoded by E10 (red). E1, E4, E5, E7, E9, E11, E12, and E13 constitute the basic component of tau protein. E0 and E14 are non-coding (white). E4a (yellow) is transcribed only in peripheral tissue. E6 and E8 are not expressed in human brain (pink). The tau isoform is composed of four areas: a N-terminal region, a proline-rich domain, a MBD, and a C-terminal projection region; (B) there are six main isoforms of tau expressed in the human brain, which are generated by alternative splicing E2, E3 and E10. There are equal amount of 3R and 4R tau in normal human brain. However, in neurodegenerative diseases, this balance is often broken.

Figure 2

Pathological changes of tau and Aβ deposition in Alzheimer’s disease as time progresses. (A) The progression of tau aggregation and deposition correlates closely with development of diseases. According to the Braak staging theory, tau pathology is first detected in the transentorhinal and entorhinal regions (Braak stages I and II), then observed in the hippocampus (stages III and IV) and later widespread in the cortex (stages V and VI); (B) while Aβ deposition starts early in Alzheimer’s disease, tau pathology is seen prior to Aβ pathology in the brain and spreads throughout the course of disease. It levels are closely linked to the timing of symptom onset.

Figure 3

Tau as a therapeutic target for neurodegenerative diseases. Tau-directed various therapeutic strategies consist of maintaining microtubule stabilization, inhibition of tau aggregation, targeting post-translational modification, clearance of tau and tau pathology, tau immunization, anti-inflammatory treatments and down-regulation of tau.