Structure and pathology of tau protein in Alzheimer disease

Abstract

Alzheimer's disease (AD) is the most common type of dementia. In connection with the global trend of prolonging human life and the increasing number of elderly in the population, the AD becomes one of the most serious health and socioeconomic problems of the present. Tau protein promotes assembly and stabilizes microtubules, which contributes to the proper function of neuron. Alterations in the amount or the structure of tau protein can affect its role as a stabilizer of microtubules as well as some of the processes in which it is implicated. The molecular mechanisms governing tau aggregation are mainly represented by several posttranslational modifications that alter its structure and conformational state. Hence, abnormal phosphorylation and truncation of tau protein have gained attention as key mechanisms that become tau protein in a pathological entity. Evidences about the clinicopathological significance of phosphorylated and truncated tau have been documented during the progression of AD as well as their capacity to exert cytotoxicity when expressed in cell and animal models. This paper describes the normal structure and function of tau protein and its major alterations during its pathological aggregation in AD.

Figure 1

Amino acid sequence of the longest tau isoform (441 amino acids). N1 and N2: the polypeptide sequences encoded by exons 2 and 3; P1 and P2: proline-rich regions; R1–R4: microtubule-binding domains encoded by exons 9–12; ²⁷⁵VQIINK²⁸⁰ and ³⁰⁶VQIVYK³¹¹: sequences with β-structure (modified by [13]).

Figure 2

Normal function of tau protein. Tau protein stabilizes microtubules through four tubulin binding domains (blue boxes) in case of the longest isoform. Binding of tau protein to the microtubules is maintained in equilibrium by coordinated actions of kinases and phosphatases. The phosphorylation of tau (pink balls) regulates its activity to bind to microtubules and can affect axonal transport. Tau protein may inhibit the plus-end-directed transport of vesicles along microtubules by kinesin.

Figure 3

Phosphorylation of tau protein. Tau self-assembles mainly through the microtubule binding domains/repeat R3 in 3R tau proteins and through R3 and R2 in 4R tau proteins (R2 (²⁷⁵VQIINK²⁸⁰) and R3 (³⁰⁶VQIVYK³¹¹) have β-structure). N-terminal and C-terminal regions to the repeats are inhibitory. Hyperphosphorylation of tau neutralizes these basic inhibitory domains, enabling tau-tau interaction (phosphorylation sites indicated by violet Ps) (modified by [15]).