Involvement of orexin nerves in early stage of Alzheimer's disease model mice and preventive effect of orexin receptor antagonists

BackgroundOrexin (OX) levels are elevated in the cerebrospinal fluid of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD).ObjectiveTo investigate the efficacy of dual OX receptor antagonists (suvorexant and lemborexant) in an early-stage AD mouse model (App-KI).MethodsOX receptor gene expression was measured. Additionally, drug distribution and effects on motor activity following single oral administration of suvorexant and lemborexant were assessed. Furthermore, cognitive function, amyloid-β (Aβ) levels and uptake by microglia in the hippocampal CA1 region were evaluated following daily administration of suvorexant and lemborexant for 60 days.ResultsOXR gene expression was highest in the lateral hypothalamus of wild-type mice and was also observed in other brain regions. OX1R gene expression was significantly increased in these brain regions in App-KI mice. In wild-type mice, brain concentrations of suvorexant peaked 20 to 40 min after administration, and those of lemborexant peaked 15 min after administration. Concentrations subsequently declined but remained detectable 24 h after administration. Additionally, motor activity decreased following the administration of either suvorexant or lemborexant; however, no difference in motor activity was observed compared to the control group 24 h later. Notably, the Y-maze test revealed that suvorexant and lemborexant mitigated cognitive impairment in App-KI mice. Furthermore, both drugs suppressed the accumulation of Aβ in the CA1 region of the hippocampus in App-KI mice. This was associated with increased Aβ uptake by activated microglia.ConclusionsThe results suggest that suvorexant and lemborexant effectively suppresses the early stages of AD.