Hypothalamic-pituitary-adrenal dysfunction in Apoe(-/-) mice: Possible role in behavioral and metabolic alterations

Several neurological diseases are frequently accompanied by dysregulation o f the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis regulates the secretion of glucocorticoids (GCs), which play important roles in diverse brain functions, including cognition, emotion, and feeding. Under physiolog ical conditions, GCs are adaptive and beneficial; however, prolonged elevat ions in GC levels may contribute to neurodegeneration and brain dysfunction . In the current study, we demonstrate that apolipoprotein E (apoE) deficie ncy results in age-dependent dysregulation of the HPA axis through a mechan ism affecting primarily the adrenal gland. Apoe(-/-) mice, which develop ne urodegenerative alterations as they age, had an age-dependent increase in b asal adrenal corticosterone content and abnormally increased plasma cortico sterone levels after restraint stress, whereas their plasma and pituitary a drenocorticotropin levels were either unchanged or lower than those in cont rols. HPA axis dysregulation was associated with behavioral and metabolic a lterations. When anxiety levels were assessed in the elevated plus maze, Ap oe(-/-) mice showed more anxiety than wild-type controls. Apoe(-/-) mice al so showed reduced activity in the open field. Finally, Apoe(-/-) mice showe d age-dependent increases in food and water intake, stomach and body weight s, and decreases in brown and white adipose tissues. These results support a key role for apoE in the tonic inhibition of steroidogenesis and HPA axis activity and have important implications for the behavioral analysis of Ap oe(-/-) mice.