Non-enzymatically glycated tau in Alzheimer's disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid beta-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 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.
Yan
S D
SD
Department of Physiology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Yan
S F
SF
Chen
X
X
Fu
J
J
Chen
M
M
Kuppusamy
P
P
Smith
M A
MA
Perry
G
G
Godman
G C
GC
Nawroth
P
P
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D005246:Feedback; D005786:Gene Expression Regulation; D006031:Glycosylation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism; D013702:Temporal Lobe / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D016564:Amyloid beta-Protein Precursor; D003574:Cytochrome c Group; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D016875:tau Proteins; D013482:Superoxide Dismutase