Raimundo Ana F, Ferreira Sofia, Martins Ivo C, Menezes Regina
iBET - Instituto de Biologia Experimental e Tecnológica, Oeiras, Portugal.
CEDOC - Chronic Diseases Research Center, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal.
Front Mol Neurosci. 2020 Mar 20;13:35. doi: 10.3389/fnmol.2020.00035. eCollection 2020.
Diabetes affects hundreds of millions of patients worldwide. Despite the advances in understanding the disease and therapeutic options, it remains a leading cause of death and of comorbidities globally. Islet amyloid polypeptide (IAPP), or amylin, is a hormone produced by pancreatic β-cells. It contributes to the maintenance of glucose physiological levels namely by inhibiting insulin and glucagon secretion as well as controlling adiposity and satiation. IAPP is a highly amyloidogenic polypeptide forming intracellular aggregates and amyloid structures that are associated with β-cell death. Data also suggest the relevance of unprocessed IAPP forms as seeding for amyloid buildup. Besides the known consequences of hyperamylinemia in the pancreas, evidence has also pointed out that IAPP has a pathological role in cognitive function. More specifically, IAPP was shown to impair the blood-brain barrier; it was also seen to interact and co-deposit with amyloid beta peptide (Aß), and possibly with Tau, within the brain of Alzheimer's disease (AD) patients, thereby contributing to diabetes-associated dementia. In fact, it has been suggested that AD results from a metabolic dysfunction in the brain, leading to its proposed designation as type 3 diabetes. Here, we have first provided a brief perspective on the IAPP amyloidogenic process and its role in diabetes and AD. We have then discussed the potential interventions for modulating IAPP proteotoxicity that can be explored for therapeutics. Finally, we have proposed the concept of a "diabetes brain phenotype" hypothesis in AD, which may help design future IAPP-centered drug developmentstrategies against AD.
糖尿病影响着全球数亿患者。尽管在对该疾病的理解和治疗选择方面取得了进展，但它仍然是全球死亡和合并症的主要原因。胰岛淀粉样多肽（IAPP），即胰淀素，是由胰腺β细胞产生的一种激素。它通过抑制胰岛素和胰高血糖素的分泌以及控制肥胖和饱腹感，有助于维持葡萄糖的生理水平。IAPP是一种高度淀粉样变性的多肽，会形成与β细胞死亡相关的细胞内聚集体和淀粉样结构。数据还表明未加工的IAPP形式与淀粉样蛋白积累的种子形成有关。除了高胰淀素血症在胰腺中的已知后果外，证据还指出IAPP在认知功能中具有病理作用。更具体地说，IAPP被证明会损害血脑屏障；在阿尔茨海默病（AD）患者的大脑中，还发现它与β淀粉样肽（Aβ）相互作用并共同沉积，可能还与 Tau 蛋白共同沉积，从而导致与糖尿病相关的痴呆。事实上，有人提出AD是由大脑中的代谢功能障碍引起的，因此它被称为3型糖尿病。在这里，我们首先简要介绍了IAPP的淀粉样变性过程及其在糖尿病和AD中的作用。然后我们讨论了可用于治疗的调节IAPP蛋白毒性的潜在干预措施。最后，我们提出了AD中“糖尿病脑表型”假说的概念，这可能有助于设计未来以IAPP为中心的抗AD药物开发策略。
