2012年12月4日 讯 /生物谷BIOON/ --近日，来自英属哥伦比亚大学和温哥华沿岸卫生局的研究者通过研究发现了一种新型分子，其可以控制负责产生斑块的蛋白质，斑块的产生是阿尔兹海默症疾病（AD）发病的信号。相关研究成果刊登于国际杂志Journal of Clinical Investigation上。
这种新型分子名为GSK3-beta，其可以激活表达蛋白质BACE1的基因，当蛋白质BACE1切断另外一种名为APP的蛋白质时，淀粉样蛋白就可以形成小纤维，进而在大脑中聚集在一起形成版块，最终杀死神经细胞。
文章中，研究者使用动物模型进行研究，发现小鼠中GSK3-beta分子效应的缺失会引发BACE1的减少以及大脑中淀粉样蛋白质水平的降低。此前研究中，研究者揭示了GSK3-beta可以激活神经元中扭曲纤维的生长。
然而，GSK3-beta分子是一种可以控制关键生理学功能的多功能酶，用于抑制该分子的药物并无差别，而且药物还可以引发一系列的副作用，包括癌症。研究者Song说，如果我们能够发现一种抑制GSK3-beta和BACE1发生特殊反应的方法，那么我们就可以更好地对待AD疾病以及抑制疾病的发展。（生物谷Bioon.com）
doi:10.1172/JCI64516
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Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes
Philip T.T. Ly1, Yili Wu1,2, Haiyan Zou1, Ruitao Wang1, Weihui Zhou2, Ayae Kinoshita3, Mingming Zhang1, Yi Yang1, Fang Cai1, James Woodgett4 and Weihong Song1,2
Deposition of amyloid β protein (Aβ) to form neuritic plaques in the brain is the pathological hallmark of Alzheimer’s disease (AD). Aβ is generated from sequential cleavages of the β-amyloid precursor protein (APP) by the β- and γ-secretases, and β-site APP-cleaving enzyme 1 (BACE1) is the β-secretase essential for Aβ generation. Previous studies have indicated that glycogen synthase kinase 3 (GSK3) may play a role in APP processing by modulating γ-secretase activity, thereby facilitating Aβ production. There are two highly conserved isoforms of GSK3: GSK3α and GSK3β. We now report that specific inhibition of GSK3β, but not GSK3α, reduced BACE1-mediated cleavage of APP and Aβ production by decreasing BACE1 gene transcription and expression. The regulation of BACE1 gene expression by GSK3β was dependent on NF-κB signaling. Inhibition of GSK3 signaling markedly reduced Aβ deposition and neuritic plaque formation, and rescued memory deficits in the double transgenic AD model mice. These data provide evidence for regulation of BACE1 expression and AD pathogenesis by GSK3β and that inhibition of GSK3 signaling can reduce Aβ neuropathology and alleviate memory deficits in AD model mice. Our study suggests that interventions that specifically target the β-isoform of GSK3 may be a safe and effective approach for treating AD.
