Amyloidogenic Amylin: Linking Type 2 Diabetes and Alzheimers Disease in Humans and Non-Humans Primates.

与年龄相关的痴呆症，特别是阿尔茨海默病(AD)和2型糖尿病(T2 DM)是工业化国家最普遍、最致残和最昂贵的疾病之一。过去几十年获得的流行病学和分子证据表明，这些疾病之间存在重叠的病理机制。阿尔茨海默病患者表现出进行性的认知衰退，表现为几个神经病理特征的出现，包括A沉积，神经纤维缠结形成，血管和代谢障碍，以及突触丢失[1]。根据临床病程和疾病分期，T2 DM患者会改变血糖调节和高血糖、胰岛素抵抗、胰岛素分泌不当和进行性细胞丢失。此外，糖尿病患者通常表现为精神灵活性降低、认知功能受损、皮质萎缩和神经元丢失[2]。1型糖尿病患者表现出同样的智力下降的事实表明，糖尿病本身而不是常见的并存疾病，如年龄、体重或高血压，是认知障碍的罪魁祸首，也是散发性AD的潜在联系。到目前为止，为了确定这种因果联系而进行的大部分研究都集中在胰岛素抵抗和葡萄糖损伤上。虽然这些因素无疑促进了疾病的进展，但大脑的葡萄糖代谢对胰岛素不敏感(3)，基于胰岛素和/或胰岛素模拟给药的临床试验一直无效，这意味着很可能涉及其他分子/途径。 AD和T2 DM的一个共同特征是，它们都是淀粉样变性疾病。在AD A中，从淀粉样前体蛋白(APP)中裂解出来的有毒多肽在海马区、皮质区以及神经血管中聚集和聚集。同样，超过92%的T2 DM患者在胰岛细胞和其他器官，如肾脏、心脏、血管和中枢神经系统(CNS)中显示胰岛淀粉样多肽(IAPP/AMYLIN)的淀粉样沉积。胰淀素是一种37个氨基酸的多肽，与胰岛素在胰腺细胞中以1：10-100的比例共同储存和共同分泌。它调节饱腹感、食物摄入量和胃排空，从而降低血糖水平和体重(4)。在胰腺中，胰淀素还调节葡萄糖诱导的胰岛素分泌和细胞增殖(4)。与人类A一样，人胰淀素具有自我聚集和形成不溶性斑块的倾向，这些斑块在细胞凋亡和T2 DM功能障碍中发挥关键作用。最近的研究表明，除T2 DM患者外，AD患者的中枢神经系统血管和实质中也存在淀粉蛋白低聚体和斑块样堆积，这些患者不仅有T2 DM患者，而且有AD无糖尿病患者(5)。这些斑块既相互独立，又与A(5)共同定位。体外研究表明，A和胰淀素的细胞毒性机制非常相似，包括膜破裂、活性氧生成、线粒体、内质网和蛋白分解损伤、诱导细胞凋亡和炎症(4，6)。此外，体外和体内实验表明，人胰淀素促进A寡聚化(7)，导致AD和T2 DM之间可能存在交叉种子机制联系。 迄今为止，为数不多的将循环胰淀素水平与阿尔茨海默病联系起来的流行病学研究未能提供明确的答案，而且已发现更高和更低水平的胰淀素与AD的较高发病率有关(8)。对这些差异的一个可能的解释是，这些研究大多是横断面的，随着病理过程的进展，胰淀素水平可能遵循类似于胰岛素的早期高和晚期低轨迹。 鉴于胰淀素可能是代谢和神经退行性疾病之间的一个重要角色，通过这个建议，我们希望通过以下方式来推进我们对它们之间的时间关系的理解： 1)从NIA热量限制纵向研究中表征非人类灵长类动物胰淀素水平随年龄的纵向变化； 2)描述巴尔的摩老龄化纵向研究参与者的胰淀素轨迹与他们的认知健康和糖尿病状况的关系； 3)测试以胰淀素为基础的对认知障碍进展的可能干预。 参考文献 1-Busche MA，Hyman BT。淀粉样蛋白和tau蛋白在阿尔茨海默病中的协同作用。Nat Neurosci。2020年10月；23(10)：1183-1193。 2-Long JM，Holtzman DM。阿尔茨海默病：病理生物学和治疗策略的最新进展。牢房。2019年10月3日；179(2)：312-339。 3-卡曼多拉·S，马特森议员。健康、衰老和神经退行性变中的大脑代谢。EMBO J.2017年6月1日；36(11)：1474-1492。 4-Kiriyama Y，Nochi H.胰淀素的作用和细胞毒性及胰岛细胞对胰淀素细胞毒性的保护作用细胞。2018年8月6日；7(8)：95。 5-Jackson K，Barisone GA，Diaz E，jin LW，DeCarli C，Despa F.Amylin在大脑中的沉积：阿尔茨海默病的第二个淀粉样蛋白？《神经网络》2013年；74：517526。 6-按M，Jung T，Knig J，Grune T，HHN A。蛋白质聚集体和衰老中的蛋白质稳定：胰淀素和细胞功能。机械老龄化开发人员。2019年1月；177：46-54。 7-张勇，唐勇，张丁，刘勇，何军，常勇，郑军，A和hIAPP之间的淀粉样杂交与阿尔茨海默病和2型糖尿病的发病机制，中国化工杂志，2021；30：225-235。 8-Mietlicki-Baase EG.阿尔茨海默病中的胰淀素：病理性多肽还是潜在的治疗方法？神经药理学。2018年7月1日；136(B点)：287-297。

Age-related forms of dementia, in particular Alzheimers disease (AD), and type 2 diabetes mellitus (T2DM) are amongst the most prevalent, disabling, and costly conditions in industrialized countries. Epidemiologic and molecular evidence acquired over the past decades identify overlapping pathological mechanisms between these conditions. Persons with AD display a progressive cognitive decline marked by the appearance of several neuropathological hallmarks including A deposition, neurofibrillary tangle formation, vascular and metabolic disturbance, and synaptic loss (1). Depending on its clinical course and disease stage, persons with T2DM have altered glycemic regulation and hyperglycemia, insulin resistance, inappropriate insulin secretion, and progressive loss of -cells. Furthermore, diabetics often display decreased mental flexibility, impaired cognitive function, cortical atrophy, and neuronal loss (2). The fact that persons with type 1 diabetes show the same mental decline, suggests that diabetes itself and not common comorbidities like age, weight, or high blood pressure, is the culprit of the cognitive dissonance and a potential link to sporadic AD. Most of the research conducted so far to define such a causative link has focused on insulin resistance and glucose impairment. While these factors undoubtedly contribute to disease progression, brain glucose metabolism is insensitive to insulin (3), and clinical trials based on insulin and/or insulin mimetic administration have been ineffective, implying other molecules/pathways are most likely involved. A common feature of AD and T2DM is that they are both amyloidogenic diseases. In AD A, the toxic peptide cleaved from the amyloid precursor protein (APP), accumulates and aggregates in hippocampal and cortical areas as well as the neurovasculature. Similarly, more than 92% of T2DM patients display amyloid deposits of islet amyloid polypeptide (IAPP/ amylin) in pancreatic islet cells and other organs like kidney, heart, vasculature, and the central nervous system (CNS). Amylin is a 37 aa peptide, co-stored and co-secreted with insulin at a ratio between 1:10-100 in pancreatic cells. It regulates satiety, food intake, and gastric emptying thus reducing blood glucose levels and body weight (4). In the pancreas amylin also regulates glucose-induced insulin secretion and the proliferation of cells (4). Like human A, human amylin shares the propensity to self-aggregate and form insoluble plaques which play a key role in cell apoptosis and T2DM dysfunction. Recently, it was shown that in addition to T2DM patients, amylin oligomers and plaque-like accumulations occur in the CNS vasculature and parenchyma of AD patients who were not diabetic not only those with T2DM but also those with AD in the absence of diabetes (5). These plaques were both independent as well as co-localized with A (5). In vitro studies have shown remarkable similarities between A and amylin cytotoxic mechanisms including membrane disruption, reactive oxygen species generation, mitochondrial, endoplasmic reticulum and proteolysis impairments, induction of apoptosis and inflammation (4,6). Furthermore, in vitro and in vivo experiments show that human amylin enhances A oligomerization (7) leading to a possible cross-seeding mechanistical link between AD and T2DM. The few epidemiological studies conducted so far to link circulating amylin levels and AD have failed to provide clear answers, and both higher and lower levels of have been found associated with higher incidence of AD (8). A possible explanation for these discrepancies is that the studies were mostly cross-sectional and amylin levels are likely to follow an early hyper- and late hypo- trajectory, similar to insulin, as the pathological process progresses. Given amylin may be an important player acting at the interface between metabolic and neurodegenerative disorders, with this proposal we wish to advance our understanding of their temporal relationships by: 1) characterizing longitudinal age-related changes of amylin levels in non-human primates from the NIA caloric restriction longitudinal study; 2) characterizing amylin trajectories in participants of the Baltimore Longitudinal Study of Aging with respect to their cognitive health and diabetic status; 3) testing possible amylin-based interventions on cognitive impairment progression. References 1-Busche MA, Hyman BT. Synergy between amyloid- and tau in Alzheimer's disease. Nat Neurosci. 2020 Oct;23(10):1183-1193. 2-Long JM, Holtzman DM. Alzheimer Disease: An Update on Pathobiology and Treatment Strategies. Cell. 2019 Oct 3;179(2):312-339. 3-Camandola S, Mattson MP. Brain metabolism in health, aging, and neurodegeneration. EMBO J. 2017 Jun 1;36(11):1474-1492. 4-Kiriyama Y, Nochi H. Role and Cytotoxicity of Amylin and Protection of Pancreatic Islet -Cells from Amylin Cytotoxicity. Cells. 2018 Aug 6;7(8):95. 5-Jackson K, Barisone GA, Diaz E, Jin LW, DeCarli C, Despa F. Amylin deposition in the brain: A second amyloid in Alzheimer disease? Ann Neurol 2013;74:517526. 6-Press M, Jung T, Knig J, Grune T, Hhn A. Protein aggregates and proteostasis in aging: Amylin and -cell function. Mech Ageing Dev. 2019 Jan;177:46-54. 7- Zhang Y, Tang Y, Zhang D, Liu Y, He J, Chang Y, Zheng J, Amyloid cross-seeding between A and hIAPP in relation to the pathogenesis of Alzheimer and type 2 diabetes, Chinese Journal of Chemical Engineering, 2021;30: 225-235. 8- Mietlicki-Baase EG. Amylin in Alzheimer's disease: Pathological peptide or potential treatment? Neuropharmacology. 2018 Jul 1;136(Pt B):287-297.