Fawver Janelle N, Ghiwot Yonatan, Koola Catherine, Carrera Wesley, Rodriguez-Rivera Jennifer, Hernandez Caterina, Dineley Kelly T, Kong Yu, Li Jianrong, Jhamandas Jack, Perry George, Murray Ian V J
Department of Physiology and Neuroscience, PO-Box 7, St George's University, St Georges, Grenada, West Indies.
Curr Alzheimer Res. 2014;11(10):928-40. doi: 10.2174/1567205011666141107124538.
Amyloid formation is the pathological hallmark of type 2 diabetes (T2D) and Alzheimer's disease (AD). These diseases are marked by extracellular amyloid deposits of islet amyloid polypeptide (IAPP) in the pancreas and amyloid β (Aβ) in the brain. Since IAPP may enter the brain and disparate amyloids can cross-seed each other to augment amyloid formation, we hypothesized that pancreatic derived IAPP may enter the brain to augment misfolding of Aβ in AD. The corollaries for validity of this hypothesis are that IAPP [1] enters the brain, [2] augments Aβ misfolding, [3] associates with Aβ plaques, and most importantly [4] plasma levels correlate with AD diagnosis. We demonstrate the first 3 corollaries that: (1) IAPP is present in the brain in human cerebrospinal fluid (CSF), (2) synthetic IAPP promoted oligomerization of Aβ in vitro, and (3) endogenous IAPP localized to Aβ oligomers and plaques. For the 4th corollary, we did not observe correlation of peripheral IAPP levels with AD pathology in either an African American cohort or AD transgenic mice. In the African American cohort, with increased risk for both T2D and AD, peripheral IAPP levels were not significantly different in samples with no disease, T2D, AD, or both T2D and AD. In the Tg2576 AD mouse model, IAPP plasma levels were not significantly elevated at an age where the mice exhibit the glucose intolerance of pre-diabetes. Based on this negative data, it appears unlikely that peripheral IAPP cross-seeds or "infects" Aβ pathology in AD brain. However, we provide novel and additional data which demonstrate that IAPP protein is present in astrocytes in murine brain and secreted from primary cultured astrocytes. This preliminary report suggests a potential and novel association between brain derived IAPP and AD, however whether astrocytic derived IAPP cross-seeds Aβ in the brain requires further research.
淀粉样蛋白形成是2型糖尿病（T2D）和阿尔茨海默病（AD）的病理标志。这些疾病的特征是胰腺中胰岛淀粉样多肽（IAPP）和大脑中淀粉样β蛋白（Aβ）的细胞外淀粉样沉积物。由于IAPP可能进入大脑，并且不同的淀粉样蛋白可以相互交叉播种以增强淀粉样蛋白的形成，我们推测胰腺来源的IAPP可能进入大脑以增强AD中Aβ的错误折叠。该假设有效性的推论是：IAPP [1]进入大脑，[2]增强Aβ错误折叠，[3]与Aβ斑块相关，最重要的是[4]血浆水平与AD诊断相关。我们证明了前三个推论：（1）IAPP存在于人类脑脊液（CSF）的大脑中，（2）合成IAPP在体外促进Aβ的寡聚化，（3）内源性IAPP定位于Aβ寡聚体和斑块。对于第四个推论，我们在非裔美国人队列或AD转基因小鼠中均未观察到外周IAPP水平与AD病理之间的相关性。在非裔美国人队列中，患T2D和AD的风险增加，在无疾病、T2D、AD或同时患有T2D和AD的样本中，外周IAPP水平无显著差异。在Tg2576 AD小鼠模型中，在小鼠表现出糖尿病前期的葡萄糖不耐受的年龄，IAPP血浆水平没有显著升高。基于这些阴性数据，外周IAPP在AD大脑中交叉播种或“感染”Aβ病理的可能性似乎不大。然而，我们提供了新的额外数据，证明IAPP蛋白存在于小鼠大脑的星形胶质细胞中，并从原代培养的星形胶质细胞中分泌。本初步报告提示大脑来源的IAPP与AD之间可能存在新的关联，然而星形胶质细胞来源的IAPP是否在大脑中交叉播种Aβ需要进一步研究。
