Identification of HPA axis dysfunction in ApoE targeted replacement mice

Abstract

The association of allele four of apoE (apoE4), a cholesterol transport protein, as a genetic risk factor for AD has been well established. However, despite knowing for over a decade that apoE4 is a risk factor for AD, the molecular mechanism behind the risk-factor activity of apoE4 remains elusive. To gain a better understanding of apoE4 biology we chose to examine the transcriptional differences associated with apoE4 expression compared to apoE3 expression in human apoE knock-in mice. Using transcriptional analysis we have investigated gene expression levels in the hippocampus of human-targeted replacement apoE3 and apoE4 knock-in mice. Results from the transcriptional profiling study showed that apoE4 mice express increased mRNA levels of glucocorticoid responsive genes and decreased levels of pituitary hormones genes compared to their apoE3 expressing counterparts. Given that glucocorticoids are known to have a negative feedback effect on the pituitary, these data indicate that apoE4 mice may have a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis. To investigate this further we examined levels of the circulating glucocorticoid hormone, corticosterone, in plasma samples taken from apoE3 and apoE4 animals. In agreement with the transcriptional profiling data, levels of plasma corticosterone were significantly up-regulated in apoE4 mice compared to apoE3 mice. Furthermore, this increase in corticosterone was accompanied by a down-regulation of plasma adrenocorticotropic hormone (ACTH), an anterior pituitary hormone. Interestingly, dysregulation of the HPA axis has been reported early in AD and disturbances of this neuroendocrine pathway are associated with hippocampal atrophy, memory impairments and neurodegeneration. It is therefore possible that the apoE4 genotype may increase the risk of AD by inducing a state of long-term chronic exposure to glucocorticoids. Taken together our results suggest that expression of apoE4 may lead to disturbances of the HPA axis and that this dysregulation may contribute to the cognitive decline and neurodegeneration that occurs in AD.