Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress.
Alzheimer's disease (AD) is a progressive neurodegenerative disease caused by genetic and non-genetic factors. Most AD cases may be triggered and promoted by non-genetic environmental factors. Clinical studies have reported that patients with AD show enhanced baseline levels of stress hormones in the blood, but their physiological significance with respect to the pathophysiology of AD is not clearly understood. Here we report that AD mouse models exposed to restraints for 2 h daily on 16 consecutive days show increased levels of beta-amyloid (Abeta) plaque deposition and commensurable enhancements in Abeta(1-42), tau hyperphosphorylation, and neuritic atrophy of cortical neurons. Repeated restraints in Tg2576 mice markedly increased metabolic oxidative stress and down-regulated the expression of MMP-2, a potent Abeta-degrading enzyme, in the brain. These stress effects were reversed by blocking the activation of the hypothalamus-pituitary-adrenal gland axis with the corticotropin-releasing factor receptor antagonist NBI 27914, further suggesting that over-activation of the hypothalamic-pituitary-adrenal axis is required for stress-enhanced AD-like pathogenesis. Consistent with these findings, corticosteroid treatments to cultured primary cortical neurons increased metabolic oxidative stress and down-regulated MMP-2 expression, and MMP-2 down-regulation was reversed by inhibition of oxidative stress. These results suggest that behavioral stress aggravates AD pathology via generation of metabolic oxidative stress and MMP-2 down-regulation.
Lee
Kang-Woo
KW
Division of Nano Sciences and Brain Disease Research Institute, Ewha Womans University, Seoul, Korea.
Kim
Jung-Bin
JB
Seo
Ji-Seon
JS
Kim
Tae-Kyung
TK
Im
Joo-Young
JY
Baek
In-Sun
IS
Kim
Kyoung-Shim
KS
Lee
Ja-Kyeong
JK
Han
Pyung-Lim
PL
D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000814:Aniline Compounds; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D003345:Corticosterone / Q000097:blood; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology*; D050050:Protein Carbonylation / Q000187:drug effects / Q000502:physiology; D011743:Pyrimidines; D017382:Reactive Oxygen Species / Q000378:metabolism; D013315:Stress, Psychological / Q000139:chemically induced / Q000503:physiopathology*; D013997:Time Factors
C471210:2-methyl-4-(N-propyl-N-cycloproanemethylamino)-5-chloro-6-(2,4,6-trichloranilino)pyrimidine; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D000814:Aniline Compounds; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D020778:Matrix Metalloproteinase 2; D003345:Corticosterone