糖原合成酶激酶3β（GSK3B）的基因变异与阿尔茨海默病的生物标志物及认知功能相关。

Genetic variants of GSK3B are associated with biomarkers for Alzheimer's disease and cognitive function.

作者信息

Kettunen Petronella, Larsson Susanna, Holmgren Sandra, Olsson Sandra, Minthon Lennart, Zetterberg Henrik, Blennow Kaj, Nilsson Staffan, Sjölander Annica

机构信息

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, the Sahlgrenska Academy at University of Gothenburg, Sweden.

Institute of Neuroscience and Physiology, Section for Clinical Neuroscience and Rehabilitation, the Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.

出版信息

J Alzheimers Dis. 2015;44(4):1313-22. doi: 10.3233/JAD-142025.

DOI:10.3233/JAD-142025

PMID:25420549

Abstract

BACKGROUND

Glycogen synthase kinase 3 beta (GSK3B) is the major kinase phosphorylating tau protein. Hyperphosphorylated tau is one of the hallmarks of Alzheimer's disease (AD). Despite extensive research, the role of GSK3B in AD pathogenesis is not fully understood.

OBJECTIVE

To evaluate possible associations between gene variants of GSK3B and risk of AD.

METHODS

Twelve GSK3B tag single-nucleotide polymorphisms (SNPs), together with the previously AD-associated rs334558, were analyzed in 583 AD patients and 673 controls. Analyses on single marker and haplotype levels were done to relate to risk of AD, Mini-Mental State Examination (MMSE) scores, and cerebrospinal fluid (CSF) biomarker levels of total tau (T-tau), hyperphosphorylated tau (P-tau181), and amyloid-β (Aβ42).

RESULTS

After correction for multiple testing, we found a number of associations of gene variants with CSF biomarker levels and cognitive function in the AD patients. Firstly, rs334558 was associated with elevated T-tau levels (pc = 0.04). Next, rs1154597 showed association with reduced Aβ42 levels (pc = 0.007). Lastly, rs3107669 was associated with lower MMSE scores (pc = 0.03). In addition, one more SNP was nominally significantly associated with reduced Aβ42 levels and another was associated with reduced MMSE.

CONCLUSION

We found GSK3B gene variants associated with cognitive function and CSF biomarkers T-tau and Aβ42. To our knowledge, this is the first time GSK3B has been associated with cognitive function or CSF biomarkers reflecting neuronal degeneration (T-tau) and brain amyloid load (Aβ42). The regulation of GSK3B needs to be investigated further, to fully understand how these GSK3B gene variants are involved in AD pathogenesis.

摘要

背景

糖原合酶激酶3β（GSK3B）是使tau蛋白磷酸化的主要激酶。tau蛋白过度磷酸化是阿尔茨海默病（AD）的特征之一。尽管进行了广泛研究，但GSK3B在AD发病机制中的作用尚未完全明确。

目的

评估GSK3B基因变异与AD风险之间的可能关联。

方法

在583例AD患者和673例对照中分析了12个GSK3B标签单核苷酸多态性（SNP）以及先前与AD相关的rs334558。进行单标记和单倍型水平分析，以关联AD风险、简易精神状态检查表（MMSE）评分以及脑脊液（CSF）生物标志物总tau（T-tau）、过度磷酸化tau（P-tau181）和淀粉样β蛋白（Aβ42）的水平。

结果

经过多重检验校正后，我们发现AD患者中一些基因变异与CSF生物标志物水平和认知功能存在关联。首先，rs334558与T-tau水平升高相关（校正P值=0.04）。其次，rs1154597与Aβ42水平降低相关（校正P值=0.007）。最后，rs3107669与较低的MMSE评分相关（校正P值=0.03）。此外，还有一个SNP名义上与Aβ42水平降低显著相关，另一个与MMSE降低相关。

结论

我们发现GSK3B基因变异与认知功能以及CSF生物标志物T-tau和Aβ42相关。据我们所知，这是首次发现GSK3B与反映神经元变性（T-tau）和脑淀粉样蛋白负荷（Aβ42）的认知功能或CSF生物标志物相关。需要进一步研究GSK3B的调节机制，以全面了解这些GSK3B基因变异如何参与AD发病机制。