A preclinical model for modulation and characterisation of neuropsychiatric disturbances in Alzheimer's disease: Development of new models and analysis methods/amyloid/Abeta. (7th December 2020) - Clement, Amalie
Abstract: Background: The events that direct the shift from asymptomatic to symptomatic Alzheimer's disease (AD) have yet to be fully characterized, however the consensus is that neuropsychiatric disturbances (NPDs) play a significant role in this. Most AD patients (80‐97%) experience at least one NPD at least once during their disease, nevertheless recognizing and treating NPDs remain a major challenge due to the poor understanding of the underlying pathology. Inflammation is thought to contribute to NPD development and ultimately exacerbate AD pathology. In AD, sleep disturbances drive neuroinflammation processes, precede clinical symptoms, and increase the risk of developing AD. Neuroinflammation can also be associated with more server NPDs and is linked to faster cognitive decline and worse prognosis. Contrary to memory and learning, which is reasonably well modelled in transgenic animals, robust preclinical models for NPDs are still lacking. We hypothesis that circadian disruption combined with chronic mild stress can introduce sleep disturbances, alter phenotypic behavior, and exacerbate AD‐related neuropathology in a common mouse model of AD. Method: We introduced socio‐environmental stress and circadian disruption to APPPS1 and wildtype (WT) littermates, to investigate NPD‐like behavior and changes in the proteome and transcriptome. Result: This approach altered normal circadian rhythm activity patterns and induced subtle NPD‐like behavior in both WT and APPPS1 mice. Furthermore, these conditions changed normal transcription of clock genes, particularly transcription levels of Cry1, Per1 and Per2 were changed in WT and APPPS1 mice. β‐amyloid plaque load was elevated in prefrontal cortex of APPPS1 mice and we observed changes in the hippocampal proteome of APPPS1 and WT compared to WT and APPPS1 mice under normal conditions. Conclusion: Although further characterization of the model is needed, we believe the model presented here can increase our understanding of the circuits responsible for NPD development in AD. This may hold the key to developing better treatments for NPDs and thus improving the quality of life for both AD patients and caregivers.