Short-term modern life-like stress exacerbates Aβ-pathology and synapse loss in 3xTg-AD mice.
Short-term modern life-like stress exacerbates Aβ-pathology and synapse loss in 3xTg-AD mice.
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DOI：
10.1111/jnc.13195
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发表时间：
2015-09
影响因子：
4.7
通讯作者：
LaFerla FM
中科院分区：
文献类型：
--
作者：
Baglietto-Vargas D;Chen Y;Suh D;Ager RR;Rodriguez-Ortiz CJ;Medeiros R;Myczek K;Green KN;Baram TZ;LaFerla FM
阿尔茨海默病（AD）是一种进行性神经系统疾病，损害老年人的记忆和其他认知功能。AD的社会和经济影响是压倒性的，并且由于人口老龄化而呈指数级上升。因此，识别AD相关的危险因素和开发更有效的治疗方法对于治愈这种神经系统疾病至关重要。目前的流行病学证据表明，生活经历，包括慢性压力，是AD的风险。然而，目前尚不清楚持续数小时的短期压力是否会影响AD的发作或进展。在这里，我们确定了短期，多模式的“现代生活样”的压力对AD发病机制和突触可塑性的小鼠轴承三个AD突变（3xTg-AD小鼠模型）的影响。我们发现，持续5小时的情绪和身体压力严重损害了野生型小鼠的记忆，并倾向于影响已经表现不佳的3xTg-AD小鼠。这种应激减少了3xTg-AD小鼠中带有突触的树突棘的数量，并通过增强AβPP加工来增加Aβ水平。因此，模拟现代生活条件的短期应激可能通过加速淀粉样蛋白病理学和减少突触数量来加剧临床前AD的认知缺陷。
Alzheimer’s disease (AD) is a progressive neurological disorder that impairs memory and other cognitive functions in the elderly. The social and financial impacts of AD are overwhelming and are escalating exponentially as a result of population aging. Therefore, identifying AD-related risk factors and the development of more efficacious therapeutic approaches are critical to cure this neurological disorder. Current epidemiological evidence indicates that life experiences, including chronic stress, are a risk for AD. However, it is unknown if short-term stress, lasting for hours, influences the onset or progression of AD. Here, we determined the effect of short-term, multi-modal ‘modern life-like’ stress on AD pathogenesis and synaptic plasticity in mice bearing three AD mutations (the 3xTg-AD mouse model). We found that combined emotional and physical stress lasting 5 h severely impaired memory in wild-type mice and tended to impact it in already low-performing 3xTg-AD mice. This stress reduced the number of synapse-bearing dendritic spines in 3xTg-AD mice and increased Aβ levels by augmenting AβPP processing. Thus, short-term stress simulating modern-life conditions may exacerbate cognitive deficits in preclinical AD by accelerating amyloid pathology and reducing synapse numbers.