tau 病小鼠模型中正常昼夜节律钟功能的破坏。

Disruption of normal circadian clock function in a mouse model of tauopathy.

机构信息

Department of Molecular Medicine, University of South Florida, Tampa, FL, USA; Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.

Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa, FL, USA; Byrd Alzheimer's Institute, University of South Florida, Tampa, FL, USA.

出版信息

Exp Neurol. 2017 Aug;294:58-67. doi: 10.1016/j.expneurol.2017.04.015. Epub 2017 Apr 28.

DOI:10.1016/j.expneurol.2017.04.015

PMID:28461004

Abstract

Disruption of normal circadian rhythm physiology is associated with neurodegenerative disease, which can lead to symptoms such as altered sleep cycles. In Alzheimer's disease (AD), circadian dysfunction has been attributed to β-amyloidosis. However, it is unclear whether tauopathy, another AD-associated neuropathology, can disrupt the circadian clock. We have evaluated the status of the circadian clock in a mouse model of tauopathy (Tg4510). Tg4510 mice display a long free-running period at an age when tauopathy is present, and show evidence of tauopathy in the suprachiasmatic nucleus (SCN) of the hypothalamus - the site of the master circadian clock. Additionally, cyclic expression of the core clock protein PER2 is disrupted in the hypothalamus of Tg4510 mice. Finally, disruption of the cyclic expression of PER2 and BMAL1, another core circadian clock protein, is evident in the Tg4510 hippocampus. These results demonstrate that tauopathy disrupts normal circadian clock function both at the behavioral and molecular levels, which may be attributed to the tauopathy-induced neuropathology in the SCN. Furthermore, these results establish the Tg4510 mouse line as a model to study how tauopathy disrupts normal circadian rhythm biology.

摘要

正常昼夜节律生理学的破坏与神经退行性疾病有关，这可能导致睡眠周期改变等症状。在阿尔茨海默病（AD）中，昼夜节律功能障碍归因于β-淀粉样蛋白。然而，尚不清楚另一种与 AD 相关的神经病理学——tau 病是否会破坏生物钟。我们已经评估了 tau 病小鼠模型（Tg4510）中生物钟的状态。Tg4510 小鼠在存在 tau 病的年龄时表现出长的自由运行周期，并在下丘脑视交叉上核（SCN）中显示出 tau 病的证据——这是主生物钟的部位。此外，Tg4510 小鼠下丘脑的核心生物钟蛋白 PER2 的周期性表达受到破坏。最后，PER2 和另一种核心生物钟蛋白 BMAL1 的周期性表达在 Tg4510 海马体中也受到破坏。这些结果表明，tau 病在行为和分子水平上都破坏了正常的生物钟功能，这可能归因于 SCN 中的 tau 病引起的神经病理学。此外，这些结果确立了 Tg4510 小鼠系作为研究 tau 病如何破坏正常昼夜节律生物学的模型。