Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-peptide.

Abstract

Paired helical filament (PHF) tau is the principal component of neurofibrillary tangles, a characteristic feature of the neurodegenerative pathology in Alzheimer's disease (AD). Post-translational modification of tau, especially phosphorylation, has been considered a major factor in aggregation and diminished microtubule interactions of PHF-tau. Recently, it has been recognized that PHF-tau is also subject to non-enzymatic glycation, with formation of advanced glycation end products (AGEs). We now show that as a consequence of glycation, PHF-tau from AD and AGE-tau generate oxygen free radicals, thereby activating transcription via nuclear factor-kappa B, increasing amyloid beta-protein precursor and release of approximately 4 kD amyloid beta-peptides. These data provide insight into how PHF-tau disturbs neuronal function, and add to a growing body of evidence that oxidant stress contributes to the pathogenesis of AD.