0298 Advancement of Tau-Mediated Neurodegeneration by Chronic Sleep Disruption

Abstract

Brainstem locus coeruleus neurons (LCn) are among the first neurons across the lifespan to evidence tau pathology, and LCn are implicated in tau propagation throughout the cortices. Yet, events influencing LCn tau are poorly understood. Activated persistently across wakefulness, LCn experience significant metabolic stress in response to chronic short sleep (CSS). Here we explored whether CSS influences LCn tau and the biochemical, neuroanatomical and/or behavioral progression in a murine model of human P301S tauopathy. P301S mice, male and female were randomized to CSS or Rest control conditions for 4 weeks. Three months later motor behaviors were assessed followed by spatial memory and then 6 months after CSS or Rest exposures, brain tisue was procured for proteim immunoblots and histology for characterization of tau post-translational modifications, tau pathology and glial reactions in the LC and entorhinal cortex (EC). LC Phosphorylated tau (P202 tau) was substantially higher in mice exposed to CSS, relative to Rest mice (t=3.4, p<0.01) and in the EC of CSS mice relative to Rest mice (t=2.5, p<0.05). CSS also increased MC1 tau in both the LC (t=2.4, p<0.01) and the EC (t=2.9, p<0.05). P301S mice exposed to CSS had markedly greater phosphorylated tau (AT8) within LC neurons than Rest P301S mice, t=5.3, p<0.001), where the AT8 signal was evident largely as tangles within LCn, but was also present and consistent with argyrophilic grains. Iba-1 % area increased significantly in the EC in CSS-exposed P301S mice (t=4.5, p<0.001). GFAP % area in the EC also increased significantly in the CSS-exposed P301S mice (t=6.3, p<0.0001). CSS mice ledge scores deteriorated from 5 to 7 mos (t=8.6, p<0.0001) and CSS mice at 7 mos evidenced poorer performances than Rest mice at 7 mos (t=2.8, p<0.05). Collectively the data demonstrate that chronic shortened sleep results in a hastening of tau degeneration, tau pathology and behavioral deterioration. The studies were performed with support from NIH grants R01 HL123331, HL 124576 and AG054104 to S.V.