Abstract
BackgroundThe 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.ResultsThe 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.ConclusionBoth 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.
Highlights
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
The application of a biological intervention to decrease cortisol levels resulted in a 7% abrogation of the acute cortisol induced decrease in hippocampal output (HO) while the intervention abrogated the chronic cortisol decrease in hippocampus activity (HA) by 22% (Figure 3, graph C)
This suggests that a biological intervention may be most effective in relation to a decrease in hippocampal atrophy associated with a chronic elevation in cortisol
Summary
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. Cortisol levels could be monitored and managed in older people, to decrease their risk of AD type hippocampal dysfunction. In the elderly, elevated plasma cortisol levels are associated with hippocampal atrophy, suggesting cortisol is involved in hippocampal dysfunction. The negative effects of elevated plasma cortisol levels on cognition in the elderly can be abrogated by blocking plasma cortisol release [7,8]. This suggests that better plasma cortisol regulation may yield improved hippocampal activity in older people
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