Abstract
<jats:p><u>Background and purpose</u> : Sleep disturbances represent a symptom, pathological contributor, and risk factor of Alzheimer’s disease (AD), with early accumulation of tau in the ascending reticular arousal system a proposed cause. Classical hypnotics are non-ideal for treating sleep loss in AD due to contraindicated side effects. Hypnotic orexin receptor antagonists (ORAs), dual ORAs (DORAs) and orexin receptor 2 antagonists (2-SORAs), promote sleep and have a more favourable side effect profile, but differ preclinically in their effects on sleep architecture. Preclinical studies indicate DORAs and 2-SORAs may ameliorate the pathology and symptoms of AD, although a 2-SORA also produced sexually dimorphic responses in the rTg4510 mouse model of tauopathy. Additionally, data on responses to 2-SORAs in AD models is limited. <u>Experimental Approach</u> : We assessed responses to 6 weeks of DORA (DORA-22) or 2-SORA (MK-1064) treatment on sleep and behaviour in male and female PS19 mice. <u>Key Results</u> : DORA-22 and MK-1064 rescued tauopathy-related sleep loss, and reduced agitation-like locomotion and stress-induced hyperthermic responses. DORA-22 and MK-1064 rescued Barnes maze cognitive performance to near WT levels in male PS19 mice. However, female PS19s receiving either DORA-22 or MK-1064 demonstrated poorer cognition compared to either WTs or their untreated controls, despite restoration of sleep. MK-1064 reduced tau pathology in the tuberomammillary nucleus. <u>Conclusions</u> : Tauopathy may sex-dependently decouple the relationship between sleep and cognition. DORAs and 2-SORAs may have therapeutic potential for improving AD outcomes associated with tauopathy. <u>Implications</u> : Future clinical studies should examine the effects of biological sex on responses to ORAs in tauopathies.</jats:p>