The Arctic/Swedish APP mutation alters the impact of chronic stress on cognition in mice

Chronic stress is a major risk factor for developing Alzheimer's disease (AD) and promotes the processing of amyloid precursor protein (APP) to β-amyloid (Aβ). However, the precise relationship of stress and disease-typical cognitive decline is presently not well understood. The aim of this study was to investigate how early life stress may affect cognition in adult mice with and without soluble Aβ pathology typical for the early stages of the disease. We focussed on sustained attention and response control, aspects of cognition mediated by the prefrontal cortex that are consistently impaired both in early AD and after chronic stress exposure. Young wild-type mice as well as transgenic arcAβ mice overexpressing the hAPParc/swe transgene were exposed to a chronic unpredictable stress paradigm (age 3-8 weeks). At 15 weeks, these mice were tested on the 5-choice serial reaction time task, a test of sustained attention and executive control. We found that, expectedly, chronic stress increased impulsive choices and impaired sustained attention in wild-type mice. However, the same treatment reduced impulsivity and did not interfere with sustained attention in arcAβ mice. These findings suggest an unexpected interaction between chronic stress and Aβ whereby Aβ-pathology caused by the hAPParc/swe mutation prevented and/or reversed stress-induced cognitive changes through mechanisms that deserve further investigation. They also indicate that Aβ, in modest amounts, may have a beneficial role for cognitive stability, for example by protecting neural networks from the impact of further physiological or behavioural stress.