BACE2 suppression promotes β-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression
BACE2 suppression promotes β-cell survival and function in a model of type 2 diabetes induced by human islet amyloid polypeptide overexpression
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DOI：
10.1007/s00018-017-2505-1
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发表时间：
2017-08-01
影响因子：
8
通讯作者：
Novials, Anna
中科院分区：
文献类型：
--
作者：
Alcarraz-Vizan, Gema;Castano, Carlos;Novials, Anna
BACE2（β 位点 APP 裂解酶 2）是一种在大脑中表达的蛋白酶，也在胰腺中表达，似乎在胰腺中发挥着生理作用。淀粉样变性疾病，包括阿尔茨海默病和 2 型糖尿病 (T2D)，都会积累异常折叠和不溶性蛋白质，从而干扰细胞功能。在 T2D 中，胰岛淀粉样多肽 (IAPP) 沉积已被证明是该疾病的致病关键特征。本研究的目的是研究 BACE2 调节对 IAPP 过表达诱导的 T2D 小鼠模型中 β 细胞改变的影响。使用携带 IAPP 人类转录物 (hIAPP-Tg) 的杂合小鼠作为模型来研究 IAPP 对 β 细胞功能的有害影响。这些动物表现出葡萄糖不耐受和胰岛素分泌受损。当与 BACE2 缺陷小鼠杂交时，与 hIAPP-Tg 小鼠相比，这些动物的葡萄糖耐量显着改善，同时胰岛素分泌增强。 BACE2 缺陷还部分恢复了 hIAPP-Tg 小鼠胰岛中观察到的基因表达变化，包括一组与炎症相关的基因。此外，纯合 hIAPP 小鼠从 8 周起出现严重高血糖，并且由于 β 细胞团的大量破坏而导致高致死率。当与BACE2-KO模型杂交时，这一过程显着减少，从而提高了动物的存活率。总而言之，BACE2 的缺失改善了 IAPP 在 β 细胞中过度表达引起的葡萄糖耐量缺陷，并促进了 β 细胞的存活。因此，靶向 BACE2 可能是改善 T2D β 细胞功能的一种有前景的治疗策略。
BACE2 (beta-site APP-cleaving enzyme 2) is a protease expressed in the brain, but also in the pancreas, where it seems to play a physiological role. Amyloidogenic diseases, including Alzheimer's disease and type 2 diabetes (T2D), share the accumulation of abnormally folded and insoluble proteins that interfere with cell function. In T2D, islet amyloid polypeptide (IAPP) deposits have been shown to be a pathogenic key feature of the disease. The aim of the present study was to investigate the effect of BACE2 modulation on beta-cell alterations in a mouse model of T2D induced by IAPP overexpression. Heterozygous mice carrying the human transcript of IAPP (hIAPP-Tg) were used as a model to study the deleterious effects of IAPP upon beta-cell function. These animals showed glucose intolerance and impaired insulin secretion. When crossed with BACE2-deficient mice, the animals presented a significant improvement in glucose tolerance accompanied with an enhanced insulin secretion, as compared to hIAPP-Tg mice. BACE2 deficiency also partially reverted gene expression changes observed in islets from hIAPP-Tg mice, including a set of genes related to inflammation. Moreover, homozygous hIAPP mice presented a severe hyperglycemia and a high lethality rate from 8 weeks onwards due to a massive destruction of beta-cell mass. This process was significantly reduced when crossed with the BACE2-KO model, improving the survival rate of the animals. Altogether, the absence of BACE2 ameliorates glucose tolerance defects induced by IAPP overexpression in the beta-cell and promotes beta-cell survival. Thus, targeting BACE2 may represent a promising therapeutic strategy to improve beta-cell function in T2D.