The effect of presenilin-1 on cerebral amyloid protein

presenilin-1对脑淀粉样蛋白的影响

• 批准号: 09835024
• 负责人: MORI Hiroshi
• 金额: $ 2.24万
• 依托单位: Osaka City University Medical School (1998)Tokyo Institute of Psychiatry (1997)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09835024/
• 关键词: Alzheimer's disease; presenilin-1; mutation; senile plague; amyloid; プレセニリン-1; 家族性アルツハイマー病; アミロイド蛋白

The effect of presenilin-1 on cerebral amyloid b proteinAmyloid beta protein (Abeta) in senile plaque and amyloid angiopathy is important not only for neuropathological hallmarker but also for the causal gene (APP) product. The possible interaction of APP and presenilin-1, another causal gene localized on chromosome 14, becomes the crutial issue for the etiology of the disease. Here we analyzed the effect of presenilin-1 on cerebral Abeta deposition in patients with Alheimer's disease.Abeta is composed of Abeta1-4O and Abeta1-42/43. Accumulating evidence shows that the causal mutation of presenilin-1 induces the higher concentration of Abeta1-42/43 than Abeta1-40. However, the present analysis showed also that the mutation causes significantly higher Abeta1-40 in addition to Abeta1-42/43 in AD patients. This may be related with the recent findings on multiple function for presenilm-1 that (1) presenhlin-1 null mice show both defects on Abeta1 production and developmental segmentation, (2) presenilin-1 could bind APP, beta-catenin and GSK3beta molecules. Thus, it is highly likely that presenilin-l affect both Abeta species. This remains to be studied using transgenic mouse model in future.

Presenilin-1 对大脑淀粉样蛋白 b 的影响老年斑和淀粉样血管病中的淀粉样蛋白 β 蛋白 (Abeta) 不仅对于神经病理标志物很重要，而且对于因果基因 (APP) 产物也很重要。 APP 与早老素-1（位于 14 号染色体上的另一个致病基因）可能存在的相互作用，成为该疾病病因学的关键问题。我们分析了早老素-1对阿尔海默病患者脑部Abeta沉积的影响。Abeta由Abeta1-4O和Abeta1-42/43组成。越来越多的证据表明，presenilin-1 的因果突变会诱导 Abeta1-42/43 浓度高于 Abeta1-40。然而，目前的分析还表明，在 AD 患者中，除了 Abeta1-42/43 之外，该突变还导致 Abeta1-40 显着升高。这可能与最近关于 presenilm-1 多种功能的发现有关，即（1）presenhlin-1 缺失小鼠在 Abeta1 产生和发育分段方面均表现出缺陷，（2）presenilm-1 可以结合 APP、β-catenin 和 GSK3beta 分子。因此，早老素-1 很可能影响两种 Abeta 物种。这还有待未来使用转基因小鼠模型进行研究。

项目成果

Tamaoka A,Fraser PE,Ishii K,Sahara N,Ozawa K,Ikeda K,Saunders AM,Komatsuzaki Y,Sherrington R,Levesque G,Yu G,Rogaeva E,Shoji S,Nee LE,Pollen DA,Hendriks L,Martini JJ,Van Brocckhoveah C,Roses AD,Farrerj LA,St.George-Hyslop PH,and Mori H: "Amyloid-β-protein

玉冈 A、弗雷泽 PE、石井 K、撒哈拉 N、小泽 K、池田 K、桑德斯 AM、小松崎 Y、谢林顿 R、莱维斯克 G、Yu G、Rogaeva E、Shoji S、Nee LE、花粉 DA、亨德里克斯 L、马蒂尼 JJ 、Van Brockhoveah C、Roses AD、Farrerj LA、St. George-Hyslop PH 和 Mori H：“淀粉样蛋白-β-蛋白

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