0200 Effects of Early-Life Sleep Disruption on Spatial Learning, Tau Burden, and Neurodegeneration in the PS19 Mouse Model of Tauopathy

Abstract

Abstract Introduction Sleep disruption is thought to increase tau hyperphosphorylation and tangle formation. This study aims to identify the impact of chronic early-life sleep disruption on late-life tau burden, neurodegeneration, and spatial memory. Methods Eight-week-old PS19 (MAPT P301S) mice and wildtype littermates were subjected to chronic daily sleep disruption (SD) or allowed to sleep ad libitum (AL) for eight weeks. SD was achieved using an automated physical stimulus every 10 seconds for 18 hours daily between ZT 0 and 18. Spatial memory testing occurred at 6, 8, and 10 months of age using the Barnes maze where latencies to find and enter the escape box were recorded on 4 consecutive days (n: WT AL=22, WT SD=21, PS19 AL=15, PS19 SD=28). Brains were subsequently collected between 10 and 14 months of age and analyzed in a subset. Tau pathology was analyzed with AT8 immunohistochemistry on paraffin sections and quantified by counting tau-positive hippocampal neurons using QuPath software. Neurodegeneration was quantified by measuring the combined area of both the lateral and third ventricles. Results Spatial memory was equivalent among all genotypes and sleep conditions at 6 months. We observed a main effect of PS19 genotype with worse spatial memory at 8 and 10 months. Notably, early life SD imparted a protective effect on spatial memory at 8 and 10 months vs ad lib sleep in PS19 mice with no effect on controls. PS19 mice experiencing early life SD showed no difference in late-life hippocampal tau burden (SD: mean 462 AT8+ neurons (SEM: 268), n=5, AL: 284 AT8+ neurons (SEM: 98), n=5, p=0.56) as well as no difference in total ventricle area (SD: mean 1.2 square mm (SEM: 0.5), n=5, AL: 2.0 square mm (SEM: 0.4), n=5, p=0.26). Conclusion Counter to our initial hypothesis, early-life SD resulted in preservation of late-life spatial memory, without changes to neurodegeneration as measured by ventricle area or changes to tau hyperphosphorylation in the hippocampus. Dissociation of tau burden and memory has been observed in models of immune modulation suggesting further investigation regarding effects of sleep disruption on immune function in the context of neurodegenerative models. Support (if any)