亨廷顿病前额皮质中丝氨酸 396 处 tau 磷酸化的年龄依赖性增加。
Age-Dependent Increase in Tau Phosphorylation at Serine 396 in Huntington's Disease Prefrontal Cortex.
机构信息
Sean M. Healey & AMG Center for ALS at Mass General, MassGeneral Brigham, Boston, MA, USA.
Department of Neurology, MassGeneral Brigham, Boston, MA, USA.
出版信息
J Huntingtons Dis. 2023;12(3):267-281. doi: 10.3233/JHD-230588.
BACKGROUND
To date, it is still controversial whether tau phosphorylation plays a role in Huntington's disease (HD), as previous studies demonstrated either no alterations or increases in phosphorylated tau (pTau) in HD postmortem brain and mouse models.
OBJECTIVE
The goal of this study was to determine whether total tau and pTau levels are altered in HD.
METHODS
Immunohistochemistry, cellular fractionations, and western blots were used to measure total tau and pTau levels in a large cohort of HD and control postmortem prefrontal cortex (PFC). Furthermore, western blots were performed to assess tau, and pTau levels in HD and control isogenic embryonic stem cell (ESC)-derived cortical neurons and neuronal stem cells (NSCs). Similarly, western blots were used to assess tau and pTau levels in HttQ111 and transgenic R6/2 mice. Lastly, total tau levels were assessed in HD and healthy control plasma using Quanterix Simoa assay.
RESULTS
Our results revealed that, while there was no difference in total tau or pTau levels in HD PFC compared to controls, the levels of tau phosphorylated at S396 were increased in PFC samples from HD patients 60 years or older at time of death. Additionally, tau and pTau levels were not changed in HD ESC-derived cortical neurons and NSCs. Similarly, total tau or pTau levels were not altered in HttQ111 and transgenic R6/2 mice compared to wild-type littermates. Lastly, tau levels were not changed in plasma from a small cohort of HD patients compared to controls.
CONCLUSIONS
Together these findings demonstrate that pTau-S396 levels increase significantly with age in HD PFC.
背景
迄今为止，tau 磷酸化是否在亨廷顿病 (HD) 中起作用仍存在争议，因为之前的研究表明，在 HD 死后大脑和小鼠模型中，磷酸化 tau (pTau) 要么没有改变，要么增加。
目的
本研究旨在确定 HD 中总 tau 和 pTau 水平是否发生改变。
方法
使用免疫组织化学、细胞分离和 Western blot 来测量大量 HD 和对照死后前额叶皮层 (PFC) 中的总 tau 和 pTau 水平。此外，还进行了 Western blot 以评估 HD 和对照同基因胚胎干细胞 (ESC) 衍生的皮质神经元和神经干细胞 (NSC) 中的 tau 和 pTau 水平。同样，使用 Western blot 评估了 HttQ111 和转基因 R6/2 小鼠中的 tau 和 pTau 水平。最后，使用 Quanterix Simoa 测定法评估了 HD 和健康对照血浆中的总 tau 水平。
结果
我们的结果表明，与对照组相比，HD PFC 中的总 tau 或 pTau 水平没有差异，但在死亡时年龄在 60 岁或以上的 HD 患者的 PFC 样本中，tau 磷酸化 at S396 的水平增加。此外，HD ESC 衍生的皮质神经元和 NSC 中 tau 和 pTau 水平没有改变。同样，与野生型同窝仔相比，HttQ111 和转基因 R6/2 小鼠中的总 tau 或 pTau 水平没有改变。最后，与对照组相比，来自一小部分 HD 患者的血浆中的 tau 水平没有改变。
结论
这些发现表明，pTau-S396 水平在 HD PFC 中随年龄显著增加。
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