JCI：宋伟宏等发现抑制阿尔茨海默病发生新靶点

重庆医科大学附属儿童医院宋伟宏教授和加拿大不列颠哥伦比亚大学的合作研究团队找到了一种全新的可干预阿尔茨海默病发病的靶点。该研究报告日前在国际《临床研究杂志》J Clin Invest.上发表。

阿尔茨海默病，俗称老年痴呆症，发病原因不清，也没有有效的预防和治疗的方法。目前认为一种叫Aβ的毒性淀粉样蛋白在大脑里形成的老年神经斑，是导致阿尔茨海默病的重要原因。宋伟宏团队的研究发现，糖原合成酶激酶3β（GSK3β）调控产生Aβ的蛋白剪切酶BACE1基因。

利用转基因动物模型实验进一步发现，抑制糖GSK3β可以减少大脑里毒性神经斑的形成，并改善阿尔茨海默病转基因小鼠的记忆障碍。该研究成果提出了阿尔茨海默病新的发病机制及药物控制靶点，有助于治疗阿尔茨海默病药物的开发。

与阿尔茨海默病相关的拓展阅读：

• Neural Regen Res. ：人参皂苷Rg1治疗阿尔茨海默病的机制
• Neural Regen Res.：苓桂术甘汤治疗阿尔茨海默病的机制
• BIB：阿尔茨海默病评估量表可能不完善（ADNI研究）
• ADvance研究发现深部脑刺激(DBS)可能治疗阿尔茨海默病
• 阿尔茨海默病病理：男女有别
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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.