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.
Highlights
The tauopathies are a class of neurodegenerative disorders characterized by hyperphosphorylation and aggregation of the microtubule-associated protein tau (MAPT) into paired helical filaments (PHFs) or straight filaments (SFs), forming neurofibrillary tangles (NFTs) in brain
Unlike amyloidbeta (Aβ) aggregation, which is associated with Alzheimer’s disease (AD), tau tangles are found in multiple neurodegenerative disorders such as progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease, dementia pugilistica, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and many other disorders including AD [1]
Using a transgenic line expressing another tau construct, designated tauE14, in which 14 S/T phosphorylation sites were mutated to glutamate to mimic phosphorylation, it was shown that flies overexpressing tauE14 and heterozygous for either Sod2n283 or TrxrΔ1 mutations displayed an increased number of apoptotic cells. In these flies, levels of tau hyperphosphorylation were not modified by the downregulation of the antioxidant enzymes. These results clearly show that heterozygous Sod or thioredoxin reductase (Trxr) mutations enhance the toxicity of tauE14 independently of tau phosphorylation levels
Summary
The tauopathies are a class of neurodegenerative disorders characterized by hyperphosphorylation and aggregation of the microtubule-associated protein tau (MAPT) into paired helical filaments (PHFs) or straight filaments (SFs), forming neurofibrillary tangles (NFTs) in brain. Mutations in the MAPT gene have been linked with several familial early-onset tauopathies [1]. In addition to tau hyperphosphorylation, a growing body of evidence suggests that oxidative stress (OS) is another component of the pathophysiology of tauopathies. 410 381 3R tau Figure 1: The MAPT gene, the variable exons, and the six tau isoforms in the adult human brain generated by alternative splicing. After a brief summary of our knowledge of tau structure and function, we review evidence suggesting that OS is both a late consequence of tau pathology paralleling the course of the disease, and an early cellular response to injuries linked to tau toxicity. We discuss the hypothesis that tau hyperphosphorylation and OS are the two key elements of a vicious circle, crucial in tau pathology
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