Abstract
BackgroundIt is hypothesized that complex interactions between multiple environmental factors and genetic factors are implicated in sporadic Alzheimer's disease (AD); however, the underlying mechanisms are poorly understood. Importantly, recent evidence reveals that expression and activity levels of the β-site APP cleaving enzyme 1 (BACE1), which initiates amyloid-β (Aβ) production, are elevated in AD brains. In this study, we investigated a molecular mechanism by which sex and stress interactions may accelerate β-amyloidogenesis and contribute to sporadic AD.ResultsWe applied 5-day restraint stress (6 h/day) to the male and female 5XFAD transgenic mouse model of AD at the pre-pathological stage of disease, which showed little amyloid deposition under non-stressed control conditions. Exposure to the relatively brief behavioral stress increased levels of neurotoxic Aβ42 peptides, the β-secretase-cleaved C-terminal fragment (C99) and plaque burden in the hippocampus of female 5XFAD mice but not in that of male 5XFAD mice. In contrast, significant changes in the parameters of β-amyloidosis were not observed in the cerebral cortex of stressed male or female 5XFAD mice. We found that this sex- and brain region-specific acceleration of β-amyloidosis was accounted for by elevations in BACE1 and APP levels in response to adverse stress. Furthermore, not only BACE1 mRNA but also phosphorylation of the translation initiation factor eIF2α (a proposed mediator of the post-transcriptional upregulation of BACE1) was elevated in the hippocampus of stressed female 5XFAD mice.ConclusionsOur results suggest that the higher prevalence of sporadic AD in women may be attributable to the vulnerability of female brains (especially, the hippocampus) to stressful events, which alter APP processing to favor the β-amyloidogenesis through the transcriptional and translational upregulation of BACE1 combined with elevations in its substrate APP.
Highlights
It is hypothesized that complex interactions between multiple environmental factors and genetic factors are implicated in sporadic Alzheimer’s disease (AD); the underlying mechanisms are poorly understood
We clearly demonstrate that the hippocampus of female 5XFAD mice shows the dramatic acceleration of b-amyloidogenesis with significantly elevated levels of both b-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE1) and APP expression following the relatively brief stress treatment, providing a molecular basis for the higher prevalence and incidence of sporadic AD in women
Behavioral stress accelerates Ab accumulation in 5XFAD mice in a sex- and brain region-dependent manner To examine the effects of adverse behavioral stress on the pathogenesis of AD, male and female 5XFAD mice at 3 months of age, which develop little or only slight amyloid deposition under normal conditions [23], were subjected to 5-day restraint stress (6 h/day)
Summary
It is hypothesized that complex interactions between multiple environmental factors and genetic factors are implicated in sporadic Alzheimer’s disease (AD); the underlying mechanisms are poorly understood. We investigated a molecular mechanism by which sex and stress interactions may accelerate b-amyloidogenesis and contribute to sporadic AD. The longevity effect might be a factor in the preponderance of women with AD, the sex difference in AD prevalence remains even after age adjustment [12,13,14]. The sex and the brain region represents a determinant of neuronal responses to stressful experience. It is important to determine whether and how gender and adverse stress may interact to modify disease progression in different brain regions of AD transgenic mice
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