Alzheimers disease (AD) is one of the most common causes of dementia world wide. Accumulation of β-amyloid (Aβ) has been implicated as a causal factor of AD. Beta secretase (BACE1) catalyses the rate limiting step in the production Aβ and has been postulated as a potential therapeutic target for AD treatment. Environmental factors, including psychological stress, accelerate the development of dementia and AD. This study examined hypothalamicpituitaryadrenal (HPA) axis activation in BACE1+/− transgenic mice following three different forms of behavioural stress.
Male BACE1+/− and wildtype (WT) mice (n=8/group) were exposed to an acute inescapable stress (elevated platform), acute escapable stress (elevated plus maze) or repeated inescapable stress (elevated plus maze for 10 days). Behaviour was assessed in the elevated plus-maze as the number of entries and time spent in the open and closed arms of the maze. Plasma corticosterone was measured by ELISA. Statistical analysis was performed using SPSS and significance set at P<0.05.
BACE1+/− mice made significantly fewer entries into the open arm of the plus maze and made fewer total entries (closed and open arms) compared to WT animals. However, there was no significant difference in the total time spent in each arm. Plasma corticosterone was comparable at baseline. All animals showed a significant increase in corticosterone following exposure to acute or repeated stress. However, BACE1+/− mice showed a heightened response to the acute inescapable stressor (elevated platform). There was no effect of genotype on thymus or adrenal weight.
These findings demonstrate that BACE1+/− mice are more anxious and have an elevated stress response to an acute psychological stressor. These results show that reduction of BACE1 levels produce a maladaptive response in the HPA axis as reported for AD patients. This suggests that BACE1 may play a role in regulation of the HPA axis independent of Aβ production.