Chronic stress induces NPD-like behavior in APPPS1 and WT mice with subtle differences in gene expression.

Neuropsychiatric disturbances (NPDs) are considered hallmarks of Alzheimer's disease (AD). Nevertheless, treatment of these symptoms has proven difficult and development of safe and effective treatment options is hampered by the limited understanding of the underlying pathophysiology. Thus, robust preclinical models are needed to increase knowledge of NPDs in AD and develop testable hypotheses and novel treatment options. Abnormal activity of the hypothalamic-pituitary-adrenal (HPA) axis is implicated in many psychiatric symptoms and might contribute to both AD and NPDs development and progression. We aimed to establish a mechanistic preclinical model of NPD-like behavior in the APPPS1 mouse model of AD and wildtype (WT) littermates. In APPPS1 and WT mice, we found that chronic stress increased anxiety-like behavior and altered diurnal locomotor activity suggestive of sleep disturbances. Also, chronic stress activated the HPA axis, which, in WT mice, remained heightened for additional 3 weeks. Chronic stress caused irregular expression of circadian regulatory clock genes (BMAL1, PER2, CRY1 and CRY2) in both APPPS1 and WT mice. Interestingly, APPPS1 and WT mice responded differently to chronic stress in terms of expression of serotonergic markers (5-HT1A receptor and MAOA) and inflammatory genes (IL-6, STAT3 and ADMA17). These findings indicate that, although the behavioral response to chronic stress might be similar, the neurobiochemical response was different in APPPS1 mice, which is an important insight in the efforts to develop safe and effective treatments options for NPDs in AD patients. Further work is needed to substantiate these findings.