重慶醫(yī)科大學(xué)附屬兒童醫(yī)院宋偉宏教授和加拿大不列顛哥倫比亞大學(xué)的合作研究團隊找到了一種全新的可干預(yù)阿爾茨海默病發(fā)病的靶點,。該研究報告日前在國際《臨床研究雜志》J Clin Invest.上發(fā)表,。
阿爾茨海默病，俗稱老年癡呆癥,，發(fā)病原因不清,，也沒有有效的預(yù)防和治療的方法。目前認為一種叫Aβ的毒性淀粉樣蛋白在大腦里形成的老年神經(jīng)斑,，是導(dǎo)致阿爾茨海默病的重要原因,。宋偉宏團隊的研究發(fā)現(xiàn)，糖原合成酶激酶3β（GSK3β）調(diào)控產(chǎn)生Aβ的蛋白剪切酶BACE1基因,。
利用轉(zhuǎn)基因動物模型實驗進一步發(fā)現(xiàn)，抑制糖GSK3β可以減少大腦里毒性神經(jīng)斑的形成,，并改善阿爾茨海默病轉(zhuǎn)基因小鼠的記憶障礙,。該研究成果提出了阿爾茨海默病新的發(fā)病機制及藥物控制靶點，有助于治療阿爾茨海默病藥物的開發(fā),。（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. Ly,1 Yili Wu,1,2 Haiyan Zou,1 Ruitao Wang,1 Weihui Zhou,2 Ayae Kinoshita,3 Mingming Zhang,1 Yi Yang,1 Fang Cai,1 James Woodgett,4 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.
