McAuley Mark T, Kenny Rose Anne, Kirkwood Thomas B L, Wilkinson Darren J, Jones Janette J L, Miller Veronica M
Henry Wellcome Building, Biogerontology Building, Institute for Ageing and Health, Newcastle University, Newcastle Upon Tyne, England, NE4 6BE, UK.
BMC Neurosci. 2009 Mar 25;10:26. doi: 10.1186/1471-2202-10-26.
The hippocampus is essential for declarative memory synthesis and is a core pathological substrate for Alzheimer's disease (AD), the most common aging-related dementing disease. Acute increases in plasma cortisol are associated with transient hippocampal inhibition and retrograde amnesia, while chronic cortisol elevation is associated with hippocampal atrophy. Thus, cortisol levels could be monitored and managed in older people, to decrease their risk of AD type hippocampal dysfunction. We generated an in silicomodel of the chronic effects of elevated plasma cortisol on hippocampal activity and atrophy, using the systems biology mark-up language (SBML). We further challenged the model with biologically based interventions to ascertain if cortisol associated hippocampal dysfunction could be abrogated.
The in silicoSBML model reflected the in vivoaging of the hippocampus and increased plasma cortisol and negative feedback to the hypothalamic pituitary axis. Aging induced a 12% decrease in hippocampus activity (HA), increased to 30% by acute and 40% by chronic elevations in cortisol. The biological intervention attenuated the cortisol associated decrease in HA by 2% in the acute cortisol simulation and by 8% in the chronic simulation.
Both acute and chronic elevations in cortisol secretion increased aging-associated hippocampal atrophy and a loss of HA in the model. We suggest that this first SMBL model, in tandem with in vitroand in vivostudies, may provide a backbone to further frame computational cortisol and brain aging models, which may help predict aging-related brain changes in vulnerable older people.
海马体对于陈述性记忆的合成至关重要，并且是阿尔茨海默病（AD）这一最常见的与衰老相关的痴呆症的核心病理基础。血浆皮质醇的急性升高与短暂性海马体抑制及逆行性遗忘有关，而慢性皮质醇升高则与海马体萎缩有关。因此，可以对老年人的皮质醇水平进行监测和管理，以降低他们发生AD型海马体功能障碍的风险。我们使用系统生物学标记语言（SBML）生成了一个关于血浆皮质醇升高对海马体活动和萎缩的慢性影响的计算机模型。我们进一步用基于生物学的干预措施对该模型进行挑战，以确定与皮质醇相关的海马体功能障碍是否可以消除。
该计算机SBML模型反映了海马体的体内衰老情况以及血浆皮质醇升高和对下丘脑-垂体轴的负反馈。衰老导致海马体活动（HA）下降12%，急性皮质醇升高使其增加到30%，慢性升高则使其增加到40%。在急性皮质醇模拟中，生物学干预使与皮质醇相关的HA下降减少了2%，在慢性模拟中减少了8%。
在该模型中，皮质醇分泌的急性和慢性升高均增加了与衰老相关的海马体萎缩及HA的丧失。我们认为，这个首个SBML模型，与体外和体内研究相结合，可能为进一步构建计算性皮质醇和脑衰老模型提供一个框架，这可能有助于预测易患AD的老年人与衰老相关的脑变化。
