The complexity of tau in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is characterized by two major pathological lesions in the brain, amyloid plaques and neurofibrillary tangles (NFTs) composed mainly of amyloid-β (Aβ) peptides and hyperphosphorylated tau, respectively. Although accumulation of toxic Aβ species in the brain has been proposed as one of the important early events in AD, continued lack of success of clinical trials based on Aβ-targeting drugs has triggered the field to seek out alternative disease mechanisms and related therapeutic strategies. One of the new approaches is to uncover novel roles of pathological tau during disease progression. This review will primarily focus on recent advances in understanding the contributions of tau to AD.

Keywords: Acetylation; Alzheimer's disease; Glia; Neurodegeneration; Neuroinflammation; Phosphorylation; Synaptic dysfunction; Tau; Tau aggregation and propagation; Tauopathies.

Fig. 1.

A brief history of tau.

Fig. 2.. Domains of 2N4R tau.

Tau protein is comprised of four primary domains, the N-terminal domain (blue), the proline-rich domain (tan), the microtubule-binding domain (pink), and the C-terminal region (green). Alternative splicing of the N-terminal and microtubule-binding domains yields six isoforms in the CNS. Repeat domains R1, R3 and R4 (light pink) are constitutive, while R2 (dark pink) is incorporated only in the three 4R isoforms. N1 and/or N2 may be skipped, but inclusion of N2 requires that N1 also be included. The final variants become: 0N3R, 1N3R, 2N3R, 0N4R, 1N4R, and 2N4R tau, the last of which is depicted here.