Abstract
Oxidative stress has been implicated in the pathogenesis and progression of several tauopathies, including Alzheimer's disease. The deposition of fibrillar inclusions made of tau protein is one of the pathological hallmarks of these disorders. Although it is becoming increasingly evident that the specific fibril structure may vary from one tauopathy to another and it is recognized that different types of isoforms (three-repeat and four-repeat tau) can be selectively deposited, little is known about the role oxidation may play in aggregation. Four-repeat tau contains two cysteines that can form an intramolecular disulfide bond, resulting in a structurally restrained compact monomer. There is discrepancy as to whether this monomer can aggregate or not. Using isolated four-repeat tau monomers (htau40) with intramolecular disulfide bonds, we demonstrate that these proteins form fibrils. The fibrils are less stable than fibrils formed under reducing conditions but are highly effective in seeding oxidized tau monomers. Conversely, a strong seeding barrier prevents incorporation of reduced tau monomers, tau mimics in which the cysteines have been replaced by alanines or serines, and three-repeat tau (htau23), a single-cysteine isoform. The barrier also holds true when seed and monomer types are reversed, indicating that oxidized and reduced tau are incompatible with each other. Surprisingly, fibrils composed of compact tau disaggregate upon reduction, highlighting the importance of the intramolecular disulfide bond for fibril stability. The findings uncover a novel binary redox switch that controls the aggregation and disaggregation of these fibrils and extend the conformational spectrum of tau aggregates.
Highlights
Oxidative stress has been implicated in the pathogenesis and progression of several tauopathies, including Alzheimer’s disease
To achieve this, purified htau40 monomers were incubated with hydrogen peroxide (H2O2) to promote disulfide bond formation and subjected to size-exclusion chromatography to separate tau species with intramolecular disulfide bonds from those with intermolecular disulfide bonds (Fig. 1A)
When oxidized htau40 monomers were subjected to MTSL labeling, the continuous wave (CW) electron paramagnetic resonance (EPR) spectrum showed only
Summary
Oxidative stress has been implicated in the pathogenesis and progression of several tauopathies, including Alzheimer’s disease. In a set of experiments, we sought to determine whether tau monomers that lack intramolecular disulfide bonds can be recruited onto htau40 Ox seeds. When these monomers were combined with 10% htau40 Ox seeds, no increase in ThT fluorescence was observed (Fig. 3A), indicating that the proteins were not recruited onto the fibrils.
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