Pro-oxidant diet enhances β/γ secretase-mediated APP processing in APP/PS1 transgenic mice.
The etiology of Alzheimer's disease (AD) is complex with oxidative stress being a possible contributory factor to pathogenesis and disease progression. TASTPM transgenic mice expressing familial AD-associated amyloid precursor protein (APPswe) and presenilin transgenes (PS1M146V) show increased brain amyloid beta (Aβ) levels and Aβ plaques from 3 months. We tested if enhancing oxidative stress through diet would accelerate Aβ-related pathology. TASTPM were fed a pro-oxidant diet for 3 months resulting in increased brain levels of protein carbonyls, increased Nrf2, and elevated concentrations of glutathione (GSH). The diet increased both amyloid precursor protein (APP) and Aβ in the cortex of TASTPM but did not alter Aβ plaque load, presenilin 1, or β-secretase (BACE1) expression. TASTPM cortical neurons were cultured under similar pro-oxidant conditions resulting in increased levels of APP and Aβ likely as a result of enhanced β/γ secretase processing of APP. Thus, pro-oxidant conditions increase APP levels and enhance BACE1-mediated APP processing and in doing so might contribute to pathogenesis in AD.
Choudhry
Fahd
F
Wolfson Centre for Age-Related Diseases, King's College London, London, UK.
Howlett
David R
DR
Richardson
Jill C
JC
Francis
Paul T
PT
Williams
Robert J
RJ
D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000821:Animal Feed; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016877:Oxidants / Q000633:toxicity*; D018384:Oxidative Stress / Q000502:physiology*; D053764:Presenilin-1 / Q000502:physiology*; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational / Q000235:genetics*
D016564:Amyloid beta-Protein Precursor; D016877:Oxidants; C508853:PSEN1 protein, human; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse