Altered sleep behavior strengthens face validity in the ArcAß mouse model for Alzheimer's disease.

Demographic changes will expand the number of senior citizens suffering from Alzheimer's disease (AD). Key aspects of AD pathology are sleep impairments, associated with onset and progression of AD. AD mouse models may provide insights into mechanisms of AD-related sleep impairments. Such models may also help to establish new biomarkers predicting AD onset and monitoring AD progression. The present study aimed to establish sleep-related face validity of a widely used mouse model of AD (ArcAß model) by comprehensively characterizing its baseline sleep/wake behavior. Chronic EEG recordings were performed continuously on four consecutive days in freely behaving mice. Spectral and temporal sleep/wake parameters were assessed and analyzed. EEG recordings showed decreased non-rapid eye movement sleep (NREMS) and increased wakefulness in transgenic mice (TG). Vigilance state transitions were different in TG mice when compared to wildtype littermates (WT). During NREMS, TG mice had lower power between 1 and 5 Hz and increased power between 5 and 30 Hz. Sleep spindle amplitudes in TG mice were lower. Our study strongly provides sleep-linked face validity for the ArcAß model. These findings extend the potential of the mouse model to investigate mechanisms of AD-related sleep impairments and the impact of sleep impairments on the development of AD.

Myelination generates aberrant ultrastructure that is resolved by microglia.

To enable rapid propagation of action potentials, axons are ensheathed by myelin, a multilayered insulating membrane formed by oligodendrocytes. Most of the myelin is generated early in development, resulting in the generation of long-lasting stable membrane structures. Here, we explored structural and dynamic changes in central nervous system myelin during development. To achieve this, we performed an ultrastructural analysis of mouse optic nerves by serial block face scanning electron microscopy (SBF-SEM) and confocal time-lapse imaging in the zebrafish spinal cord. We found that myelin undergoes extensive ultrastructural changes during early postnatal development. Myelin degeneration profiles were engulfed and phagocytosed by microglia using exposed phosphatidylserine as one "eat me" signal. In contrast, retractions of entire myelin sheaths occurred independently of microglia and involved uptake of myelin by the oligodendrocyte itself. Our findings show that the generation of myelin early in development is an inaccurate process associated with aberrant ultrastructural features that require substantial refinement.