Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.
Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.
Br J Pharmacol. 2024 Jan;181(1):87-106. doi: 10.1111/bph.16212. Epub 2023 Sep 8.
Tau pathology contributes to a bidirectional relationship between sleep disruption and neurodegenerative disease. Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown.
Three 8-week experiments were conducted with wild-type and rTg4510 mice after age of onset of hyperarousal (4.5 months): (1) Tau transgene suppression with doxycycline (200 ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50 mg·kg ·day ); or (3) Active phase non-NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX ) receptor antagonist MK-1064 (40 mg·kg ·day ). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and/or immunohistochemistry.
Tau transgene suppression improved tauopathy and hippocampal-dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX receptor antagonism induced only short-lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau- and sex-dependent disruption of OX receptor signalling.
Pharmacologically reducing hyperarousal corrects tau-induced sleep/wake and cognitive deficits. Tauopathy causes sex-dependent disruptions of OX receptor signalling/function, which may have implications for choice of hypnotic therapeutics in tauopathies.
tau 病理学导致了睡眠障碍和神经退行性疾病之间的双向关系。tau 转基因 rTg4510 小鼠模型表现出 tau 病症状，包括睡眠/觉醒障碍，表现为明显的过度兴奋。这种表型可以通过早期转基因抑制来预防；然而，发病后是否可以挽救过度兴奋尚不清楚。
在 rTg4510 小鼠出现过度兴奋（4.5 个月）后，进行了三个为期 8 周的实验：（1）使用强力霉素（200ppm）抑制 tau 转基因；（2）使用双重食欲素受体拮抗剂苏沃雷生（50mg·kg·day）增强非快速眼动（NREM）睡眠的不活跃期；（3）使用选择性食欲素 2（OX2）受体拮抗剂 MK-1064（40mg·kg·day）增强 NREM 和快速眼动（REM）睡眠的活跃期。使用多导睡眠描记术评估睡眠，使用巴恩斯迷宫评估认知，使用免疫印迹和/或免疫组织化学评估 tau 病理学。
tau 转基因抑制改善了 tau 病和海马依赖性空间记忆，但没有改变过度兴奋。REM 睡眠缺陷的药物治疗未能改善空间记忆或 tau 病理学。相反，通过 OX 受体拮抗作用增加 NREM 和 REM 睡眠来正常化过度兴奋，独立于 tau 病理学，仅在雄性 rTg4510 小鼠中恢复了空间记忆。OX 受体拮抗作用仅在雌性 rTg4510 小鼠中引起短暂的催眠反应，并且不能改善空间记忆，表明 tau 和性别依赖性的 OX 受体信号转导破坏。
药物降低过度兴奋纠正了 tau 引起的睡眠/觉醒和认知缺陷。tau 病引起了 OX 受体信号转导/功能的性别依赖性破坏，这可能对 tau 病中的催眠治疗选择有影响。
