日本大阪生物科學(xué)研究所等機構(gòu)的研究人員在最新一期美國《國家科學(xué)院學(xué)報》上發(fā)表論文稱,，貝塔淀粉樣蛋白堆積可導(dǎo)致阿爾茨海默氏癥,，而腦脊髓液中分泌的一種酶可抑制這種蛋白的堆積。
據(jù)日本媒體報道,，在實驗中，研究人員向貝塔淀粉樣蛋白中添加這種酶并發(fā)現(xiàn),，加入的酶和貝塔淀粉樣蛋白緊密結(jié)合在一起,，此后貝塔淀粉樣蛋白就不能聚集、堆積,。
研究人員還發(fā)現(xiàn),，如果改變實驗鼠的基因，使它們不能分泌上述酶,，實驗鼠腦內(nèi)的貝塔淀粉樣蛋白堆積量就會達到正常實驗鼠的３倍,。而腦內(nèi)這種酶分泌量增大的實驗鼠，其貝塔淀粉樣蛋白的量可減少到只有正常情況的幾分之一,。
研究人員認(rèn)為,，通過分析這種酶的分泌量有望預(yù)測阿爾茨海默氏癥何時發(fā)病，也可利用這種酶開發(fā)新的治療藥物,。
阿爾茨海默氏癥是一種中樞神經(jīng)系統(tǒng)疾病,，可導(dǎo)致患者神經(jīng)細胞死亡，腦部逐漸萎縮,，出現(xiàn)認(rèn)知障礙和記憶力損害,。日本國內(nèi)的該病患者約有２００萬人。很多醫(yī)學(xué)專家認(rèn)為,，貝塔淀粉樣蛋白堆積會引發(fā)阿爾茨海默氏癥,。
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: [email protected]
英文全文鏈接：www.pnas.org/cgi/content/full/104/10/4159
