Tau Hyperphosphorylation and Oxidative Stress, a Critical Vicious Circle in Neurodegenerative Tauopathies?

Abstract

Hyperphosphorylation and aggregation of the microtubule-associated protein tau in brain, are pathological hallmarks of a large family of neurodegenerative disorders, named tauopathies, which include Alzheimer's disease. It has been shown that increased phosphorylation of tau destabilizes tau-microtubule interactions, leading to microtubule instability, transport defects along microtubules, and ultimately neuronal death. However, although mutations of the MAPT gene have been detected in familial early-onset tauopathies, causative events in the more frequent sporadic late-onset forms and relationships between tau hyperphosphorylation and neurodegeneration remain largely elusive. Oxidative stress is a further pathological hallmark of tauopathies, but its precise role in the disease process is poorly understood. Another open question is the source of reactive oxygen species, which induce oxidative stress in brain neurons. Mitochondria have been classically viewed as a major source for oxidative stress, but microglial cells were recently identified as reactive oxygen species producers in tauopathies. Here we review the complex relationships between tau pathology and oxidative stress, placing emphasis on (i) tau protein function, (ii) origin and consequences of reactive oxygen species production, and (iii) links between tau phosphorylation and oxidative stress. Further, we go on to discuss the hypothesis that tau hyperphosphorylation and oxidative stress are two key components of a vicious circle, crucial in neurodegenerative tauopathies.

Figure 1

The MAPT gene, the variable exons, and the six tau isoforms in the adult human brain generated by alternative splicing. The constitutively spliced exons are shown in beige. E0, E4a, E6, E8, and E14 are not transcribed in human brain. Alternative mRNA splicing of E2 (green), E3 (yellow), and E10 (red) generates six tau isoforms ranging from 352 to 441 aminoacids. Three isoforms have four repeats each (4 repeat) and three isoforms have three repeats each (3 repeat). The repeats are shown with R (R1 to R4). The exons and introns are not shown to scale.

Figure 2

Schematic representation of the distribution of tau phosphorylation sites on the longest tau isoform (441 amino acids). The two amino-terminal inserts are demonstrated by E2 and E3. The microtubule-binding domains are represented with R(1–4). Physiologic tau phosphorylation comprises approximately 10 phosphorylated residues. The physiologically phosphorylated residues are shown in purple and cluster in the proline-rich domain (PRD) and in the C-terminal region. The number of phosphorylated residues rises to 45 on the longest tau isoform from Alzheimer brain with the appearance of phosphorylated residues shown in red. The two amino-terminal inserts and repeat regions are not physiologically phosphorylated in adult human brain. A number of phosphorylation sites are detected in both regions on the longest tau isoform from Alzheimer brain.