Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced β-cell apoptosis in h-IAPP transgenic mice
Toxic human islet amyloid polypeptide (h-IAPP) oligomers are intracellular, and vaccination to induce anti-toxic oligomer antibodies does not prevent h-IAPP-induced β-cell apoptosis in h-IAPP transgenic mice
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DOI：
10.2337/db06-1579
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发表时间：
2007-05-01
期刊：
影响因子：
7.7
通讯作者：
Butler, Peter C.
中科院分区：
文献类型：
--
作者：
Lin, Chia-Yu;Gurlo, Tatyana;Butler, Peter C.
目的：2型糖尿病胰岛的特征是β细胞缺陷、β细胞凋亡增加和胰岛淀粉样蛋白多肽（IAPP）衍生的胰岛淀粉样蛋白。淀粉样蛋白低聚物的毒性形式与淀粉样蛋白原纤维不同，并且比淀粉样蛋白原纤维小，并且通过破坏膜起作用。使用与毒性IAPP寡聚体结合的抗体（但不是IAPP单体或原纤维）和基于疫苗接种的方法，我们试图确定IAPP毒性寡聚体是否在细胞内或细胞外形成，以及接种以诱导抗毒性寡聚体抗体是否阻止人IAPP（h-IAPP）转基因小鼠中IAPP诱导的细胞凋亡。IAPP转基因小鼠模型，并通过免疫组织化学检查毒性寡聚体。用阿尔茨海默氏病β蛋白（A β P1-40）的毒性寡聚体接种相同的鼠模型，并监测抗寡聚体滴度，以及血糖和胰岛病理学。疫苗诱导高滴度的抗h-IAPP毒性寡聚体在两个转基因模型，但β-细胞凋亡，如果有的话，进一步增加在接种疫苗的小鼠，使既不损失的β-细胞质量，也不糖尿病发作是delayed.CONCLUSIONS - IAPP毒性寡聚体形成在h-IAPP转基因小鼠模型，和抗毒性寡聚体抗体不阻止h-IAPP诱导的β-细胞凋亡。这些数据表明，在预防2型糖尿病方面，预防h-IAPP寡聚体形成可能比基于疫苗接种的方法更有用。
OBJECTIVE - Islets in type 2 diabetes are characterized by a deficit in beta-cells, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). The toxic form of amyloidogenic protein oligomers are distinct and smaller than amyloid fibrils and act by disrupting membranes. Using antibodies that bind to toxic IAPP oligomers (but not IAPP monomers or fibrils) and a vaccination-based approach, we sought to establish whether IAPP toxic oligomers form intra- or extracellularly and whether vaccination to induce anti-toxic oligomer antibodies prevents IAPP-induced apoptosis in human IAPP (h-IAPP) transgenic mice.RESEARCH DESIGN AND METHODS - Pancreas was sampled from two h-IAPP transgenic mouse models and examined by immunohistochemistry for toxic oligomers. The same murine models were vaccinated with toxic oligomers of Alzheimer (3 protein (A beta P1-40) and anti-oligomer titers, and blood glucose and islet pathology were monitored.RESULTS - Toxic oligomers were detected intracellularly in similar to 20-40% of h-IAPP transgenic beta-cells. Vaccine induced high titers of anti-h-IAPP toxic oligomers in both transgenic models, but beta-cell apoptosis was, if anything, further increased in vaccinated mice, so that neither loss of beta-cell mass nor diabetes onset was delayed.CONCLUSIONS - IAPP toxic oligomers form in h-IAPP transgenic mouse models, and anti-toxic oligomer antibodies do not prevent h-IAPP-induced beta-cell apoptosis. These data suggest that prevention of h-IAPP oligomer formation may be more useful than a vaccination-based approach in the prevention of type 2 diabetes.