The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice.
The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice.
复制标题
载脂蛋白E缺乏对人胰岛淀粉样多肽转基因小鼠胰岛淀粉样蛋白沉积的影响。
DOI：
10.1007/s00125-002-0984-5
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Kahn,SE
中科院分区：
文献类型：
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作者：
Vidal,J;Verchere,CBruce;Andrikopoulos,S;Wang,F;Hull,RL;Cnop,M;Olin,KL;LeBoeuf,RC;O'Brien,KD;Chait,A;Kahn,SE
目的/假设：85%以上的2型糖尿病患者存在胰岛淀粉样蛋白沉积，并被认为是致病性的。胰岛淀粉样多肽（IAPP），这些沉积物的独特成分，在体内转化为淀粉样纤维的机制尚不清楚。IAPP的氨基酸序列是关键的，但不足以形成折叠片层。由于载脂蛋白E（apoE）是胰岛淀粉样蛋白沉积物的另一种组分，在阿尔茨海默病的淀粉样蛋白形成中起关键作用，我们假设apoE在胰岛淀粉样蛋白形成中起重要作用。（hIAPP+/0）与apoE缺陷（apoE-/-）小鼠杂交，并随访12个月，此时胰岛淀粉样蛋白的患病率和严重程度，结果：1年后，IAPP +/0小鼠中apoE +/+、apoE+/-或apoE-/-小鼠胰岛淀粉样蛋白的患病率和严重程度相当。在葡萄糖耐量，血脂异常或胰腺内容物或血浆浓度的hIAPP和/或IRI的变化的差异并没有占这些findings.Conclusion/interpretation.Our数据表明，不同于在阿尔茨海默病的特征性脑中的局部淀粉样变性，载脂蛋白E是不是2型糖尿病的转基因小鼠模型的胰岛淀粉样蛋白形成的关键。这些结果表明，局部淀粉样蛋白形成的机制可能不同的淀粉样蛋白相关疾病。因此，靶向apoE的治疗策略可能不适用于不同的淀粉样蛋白相关疾病的患者。
AbstractAims/hypothesis.Islet amyloid deposits are present in over 85% of Type 2 diabetic patients and have been suggested to be pathogenic. The mechanism that converts islet amyloid polypeptide (IAPP), the unique component of these deposits, into amyloid fibrils in vivo is not known. The amino acid sequence of IAPP is critical but insufficient for beta-pleated sheet formation. As apolipoprotein E (apoE), another component of islet amyloid deposits, plays a critical role in amyloid formation in Alzheimer's disease, we hypothesised that apoE could play an important role in islet amyloid formation.Methods.Transgenic mice expressing the human form of IAPP (hIAPP+/0) were crossbred with apoE deficient (apoE–/–) mice and followed for 12 months, at which time the prevalence and severity of islet amyloid, as well as plasma glucose, hIAPP, immunoreactive insulin (IRI) and lipid concentrations were measured.Results.The prevalence and severity of islet amyloid after one year of follow up were comparable amonghIAPP+/0mice that wereapoE+/+,apoE+/–orapoE–/–. Differences in glucose tolerance, lipid abnormalities or changes in pancreatic content or plasma concentrations of hIAPP and/or IRI did not account for these findings.Conclusion/interpretation.Our data shows that, unlike in the localized amyloidosis in the brain characteristic of Alzheimer's disease, apoE is not critical for islet amyloid formation in a transgenic mouse model of Type 2 diabetes mellitus. These results indicate that the mechanisms of localised amyloid formation probably vary among different amyloid-associated disorders. Therefore, therapeutic strategies targeting apoE might not apply equally to patients with different amyloid associated diseases.