Halloy Nicklaus R, Formanowicz Megan, Pham Nguyen Nhi Lien, Hoyt Kari R, Obrietan Karl
Department of Neuroscience, Ohio State University, Columbus, OH, USA.
Division of Pharmaceutics and Pharmacology, Ohio State University, Columbus, OH, USA.
bioRxiv. 2025 Jun 8:2025.06.06.655835. doi: 10.1101/2025.06.06.655835.
Tauopathies are a group of neurodegenerative disorders caused by the misfolded microtubule-associated protein tau (MAPT), leading to its abnormal accumulation and hyperphosphorylation, and resulting in neuronal dysfunction and death. Tauopathy patients also experience disruptions to circadian rhythms of behavior and sleep. The connection between tau pathology and circadian dysfunction is not well understood, especially regarding the role of the suprachiasmatic nucleus (SCN), the brain's central circadian pacemaker. Here, we conducted histological and functional analyses of the SCN in the PS19 (Prnp-huMAPT*P301S) mouse model of tauopathy. The SCN of PS19 mice had accumulation of phosphorylated tau as early as 2 months of age, and tau pathology was detected in both major neuronal subpopulations of the SCN: VIPergic (core) and AVPergic (shell) neurons. To assess SCN timing and entrainment properties, daily locomotor activity was monitored in PS19 and wild-type (WT) mice from 3 to 11 months-of-age. Activity profiles, rates of re-entrainment to changes in the light/dark cycle, and intrinsic circadian timing properties were unchanged in PS19 mice compared to age-matched WT mice. Finally, profiling circadian gene expression in tau fibril-seeded SCN explants from PS19 and WT mice did not reveal differences in network-level oscillator properties. Together, these findings suggest that tau pathology within the SCN is not sufficient to trigger marked disruptions of core circadian timing mechanisms in this tauopathy model. Further, these results raise the possibility that circadian disruptions in tauopathies arise from dysfunction in SCN-gated output pathways or downstream clock-gated circuits rather than the SCN oscillator itself.
tau蛋白病是由错误折叠的微管相关蛋白tau（MAPT）引起的一组神经退行性疾病，导致其异常积累和过度磷酸化，进而导致神经元功能障碍和死亡。tau蛋白病患者的行为和睡眠昼夜节律也会受到干扰。tau蛋白病变与昼夜节律功能障碍之间的联系尚未完全清楚，尤其是关于视交叉上核（SCN）的作用，它是大脑的中央昼夜节律起搏器。在此，我们对tau蛋白病的PS19（Prnp-huMAPT*P301S）小鼠模型的SCN进行了组织学和功能分析。PS19小鼠的SCN早在2个月大时就有磷酸化tau蛋白的积累，并且在SCN的两个主要神经元亚群中都检测到了tau蛋白病变：表达血管活性肠肽（VIP）的（核心）神经元和表达精氨酸加压素（AVP）的（壳）神经元。为了评估SCN的计时和同步特性，在3至11月龄的PS19和野生型（WT）小鼠中监测每日运动活动。与年龄匹配的WT小鼠相比，PS19小鼠的活动模式、对光/暗周期变化的重新同步率和内在昼夜节律计时特性没有变化。最后，对来自PS19和WT小鼠的tau原纤维接种的SCN外植体中的昼夜节律基因表达进行分析，未发现网络水平振荡器特性存在差异。总之，这些发现表明，在这个tau蛋白病模型中，SCN内的tau蛋白病变不足以引发核心昼夜节律计时机制的明显破坏。此外，这些结果增加了一种可能性，即tau蛋白病中的昼夜节律紊乱是由SCN门控输出通路或下游时钟门控电路功能障碍引起的，而不是由SCN振荡器本身引起的。
