Behavioral stress accelerates plaque pathogenesis in the brain of Tg2576 mice via generation of metabolic oxidative stress

Kang Woo Lee, Jung Bin Kim, Ji Seon Seo, Tae Kyung Kim, Joo Young Im, In Sun Baek, Kyoung Shim Kim, Ja Kyeong Lee, Pyung Lim Han

Research output: Contribution to journalArticlepeer-review

114 Scopus citations

Abstract

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 β-amyloid (Aβ) plaque deposition and commensurable enhancements in Aβ(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 Aβ-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.

Original languageEnglish
Pages (from-to)165-175
Number of pages11
JournalJournal of Neurochemistry
Volume108
Issue number1
DOIs
StatePublished - Jan 2009

Keywords

  • Alzheimer's disease
  • Behavioral stress
  • Matrix metalloproteinase-2
  • Plaque pathogenesis
  • Reactive oxygen species

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