PNAS：日本发现抑制阿尔茨海默氏症病因的酶
日本大阪生物科学研究所等机构的研究人员在最新一期美国《国家科学院学报》上发表论文称，贝塔淀粉样蛋白堆积可导致阿尔茨海默氏症，而脑脊髓液中分泌的一种酶可抑制这种蛋白的堆积。
据日本媒体报道，在实验中，研究人员向贝塔淀粉样蛋白中添加这种酶并发现，加入的酶和贝塔淀粉样蛋白紧密结合在一起，此后贝塔淀粉样蛋白就不能聚集、堆积。
研究人员还发现，如果改变实验鼠的基因，使它们不能分泌上述酶，实验鼠脑内的贝塔淀粉样蛋白堆积量就会达到正常实验鼠的３倍。而脑内这种酶分泌量增大的实验鼠，其贝塔淀粉样蛋白的量可减少到只有正常情况的几分之一。
研究人员认为，通过分析这种酶的分泌量有望预测阿尔茨海默氏症何时发病，也可利用这种酶开发新的治疗药物。
阿尔茨海默氏症是一种中枢神经系统疾病，可导致患者神经细胞死亡，脑部逐渐萎缩，出现认知障碍和记忆力损害。日本国内的该病患者约有２００万人。很多医学专家认为，贝塔淀粉样蛋白堆积会引发阿尔茨海默氏症。
部分英文原文：
Published online before print February 27, 2007, 10.1073/pnas.0611236104
PNAS | March 6, 2007 | vol. 104 | no. 10 | 4159-4164
Regulation of Alzheimer's disease amyloid-
formation by casein kinase I
Marc Flajolet*, Gen He*, Myriam Heiman*, Angie Lin*, Angus C. Nairn*,
, and Paul Greengard*,
*Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10021; and Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508
Contributed by Paul Greengard, January 5, 2007 (received for review November 30, 2006)
Alzheimer's disease (AD) is associated with accumulation of the neurotoxic peptide amyloid-
(A), which is produced by sequential cleavage of amyloid precursor protein (APP) by the aspartyl protease -secretase and the presenilin-dependent protease 
-secretase. An increase of casein kinase 1 (CK1) expression has been described in the human AD brain. We show, by using in silico analysis, that APP, -secretase, and -secretase subunits contain, in their intracellular regions, multiple CK1 consensus phosphorylation sites, many of which are conserved among human, rat, and mouse species. Overexpression of constitutively active CK1
, one of the CK1 isoforms expressed in brain, leads to an increase in A peptide production. Conversely, three structurally dissimilar CK1-specific inhibitors significantly reduced endogenous A peptide production. By using mammalian cells expressing the C-terminal fragment of APP, it was possible to demonstrate that CK1 inhibitors act at the level of -secretase cleavage. Importantly, Notch cleavage was not affected. Our results indicate that CK1 represents a therapeutic target for prevention of A formation in AD.
-cleavage | neurodegenerative | amyloid precursor protein
Author contributions: M.F., G.H., M.H., A.C.N., and P.G. designed research; M.F., G.H., and A.L. performed research; M.F., A.L., and P.G. analyzed data; and M.F., A.C.N., and P.G. wrote the paper.
The authors declare no conflict of interest.
To whom correspondence should be addressed. E-mail: greengard@rockefeller.edu
英文全文链接：www.pnas.org/cgi/content/full/104/10/4159
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