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

Background: Orexin (OX) levels are elevated in the cerebrospinal fluid of patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Objective: To investigate the efficacy of dual OX receptor antagonists (suvorexant and lemborexant) in an early-stage AD mouse model (App-KI). Methods: OX 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. Results: OXR 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. Conclusions: The results suggest that suvorexant and lemborexant effectively suppresses the early stages of AD.