Non-enzymatically glycated tau in alzheimer’s disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid (β-peptide

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 ACE-tau generate oxygen free radicals, thereby activating transcription via nuclear factor-KB, increasing amyloid β-protein precursor and release of ~4 kD amyloid p-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.