Measurement of brain clearance and its daytime-dependent efficacy in mice.

Abstract

Amyloid β (Aβ) plaques are recognized as a main pathological hallmark of Alzheimer´s disease (AD). One important cause for Aβ-plaque formation may be a persistent dysbalance between Aβ production and clearance. In the last years, the so called glymphatic system was identified as main contributor to Aβ clearance from the brain through glia-mediated perivascular networks. Interestingly, the functionality and efficacy of glymphatic clearance is closely related to circadian rhythm integrity. Understanding the correlation between sleep-wake-cycle and its influence on glymphatic clearance will lead to a refinement in future preclinical and clinical AD investigations. To study daytime-dependent changes in brain clearance we established an in vivo protocol to assess the dispersion of a fluorescent dye injected into the hippocampal parenchyma of C57BL6J mice on begin (6 am, dusk for the mice, n = 6) and end (6 pm, dawn for the mice, n = 6) of the light period. Brains were explanted 1 h (n =3 per group) or 3 h (n = 3 per group) post injection and dye dispersion was histologically assessed (Figure 1). First data point to an effect of sleep-wake-cycle on brain clearance, as indicated by elevated fluorescent dye dispersion in the evening. Due to the time delay caused by the Corona pandemic, histologic analyses are still ongoing. However, our results will be ready to be presented at the AAIC 2021. Our data suggest an experimental approach to study day-time dependency of brain clearance in mouse models of AD. We hope that these data will encourage researchers to pay more attention to circadian rhythmicity when studying AD in basic and clinical research.