2012年8月23日 訊 /生物谷BIOON/ --一 在Ruhr大學Medizinisches蛋白質組學中心的Thorsten Müller博士的帶領下，研究人員目前發表論文揭示了阿爾茨海默氏症患者的大腦中的異常蛋白沉積是如何破壞神經細胞之間的信號。研究人員報告說，阿爾茨海默氏症患者大腦中的異常蛋白質的沉積會破壞神經細胞之間的信號聯繫。在體外細胞培養中，研究人員改變了阿爾茨海默氏症APP蛋白及相關蛋白的量，然後分析這一操作是如何影響細胞中其他蛋白質的。其結果是：APP存在的量與神經遞質的生成、神經細胞之間的溝通必不可少的一種酶的量有關。
蛋白質組學一次性分析細胞所有蛋白質澱粉樣蛋白斑是阿爾茨海默氏病的一個特徵。它們組成了所謂的澱粉樣蛋白前體蛋白APP的裂解產物，APP在阿爾茨海默氏症患者大腦中是過量的。APP在健康人中扮演什麼樣的角色，為什麼澱粉樣蛋白會異常堆積擾亂正常運作的大腦，這些在很大程度上仍然不清楚。為了了解APP的功能，RUB研究人員建立了一種新的細胞模型。新的細胞只產生極少量的APP。研究人員通過質譜分析極少量APP的產生對這些細胞的其他蛋白質有什麼樣的影響。通過這種方法，研究人員確定APP的產生對超過2000個蛋白有影響，並確定了這些蛋白的濃度。他們正在尋找一種特定的分子，其濃度在新建成的低APP細胞中與含有正常量的APP細胞中是具有差異的。
不正常的蛋白質能夠抑制神經遞質的生成。Thorsten Müller說：一個候選蛋白引起了我們的注意，這就是蛋氨酸腺苷酶II，簡稱MAT2A。研究發現這種酶是神經遞質生成的關鍵。低APP的細胞含有比正常量的APP細胞較少的MAT2A。為了確認「老年痴呆症蛋白質」APP和神經遞質MAT2A之間的聯繫，該研究小組利用阿爾茨海默氏症死者和健康人的大腦組織樣本。發現在阿爾茨海默氏症患者的組織中MAT2A比健康人大腦樣本中要少。（生物谷：Bioon.com）
編譯自：'Alzheimer protein' seems to slow down neurotransmitter production
The APP family members are key players in S-adenosylmethionine formation by MAT2A and modify BACE1 and PSEN1 gene expression - relevance for Alzheimer's disease
A. Schrtter, K. Pfeiffer, F. El Magraoui, H. Platta, R. Erdmann, Helmut E. Meyer, R. Egensperger, K. Marcus, T. Müller
A central hallmark of Alzheimers disease (AD) are senile plaques mainly composed of [beta] amyloid, which is a cleavage product of the amyloid precursor protein (APP). The physiological function of APP and its family members APLP1 and APLP2 is poorly understood. In order to fill this gap, we established a cell-culture based model with simultaneous knockdown of all members of the family. A comprehensive proteome study of the APP/APLP1/APLP2 knockdown cell lysates vs. controls revealed significant protein abundance changes of more than 30 proteins. Targeted validation of selected candidates by immunoblotting supported the significant down-regulation of the methionine adenosyltransferase II, alpha (MAT2A) as well as of peroxiredoxin 4 (PRDX4) in the knockdown cells. Moreover, MAT2A was significantly down-regulated at the mRNA level as well. MAT2A catalyzes the production of S-adenosylmethionine (SAM) from methionine and ATP, which plays a pivotal role in the methylation of neurotransmitters, DNA, proteins, and lipids. MAT2A-dependent significant up-regulation of SAM was also detectable in the knockdown cells compared to controls. Our results point to a role of the APP family proteins in cellular methylation mechanisms and fit to findings of disturbed SAM levels in tissue and CSF of Alzheimer disease patients vs. controls. Importantly, methylation plays a central role for neurotransmitter generation like acetylcholine pointing to a crucial relevance of our findings for AD. In addition, we identified differential gene expression of BACE1 and PSEN1 in the knockdown cells, which is possibly a consequence of MAT2A deregulation and may indicate a self regulatory mechanism.