Role of Systemic Amylin Dyshomeostasis in Alzheimer's Disease

摘要 我们认为，阿尔茨海默病的早期和可能的可治疗因素在多因素病因中起作用 (AD)涉及胰淀素的代谢紊乱，胰淀素是一种跨越血脑屏障的胰腺激素，具有 与β-淀粉样蛋白(A-β)多肽类似的淀粉样变性。这一假设得到了 我们实验室和其他实验室最近的研究表明，AD患者的大脑中有大量的胰淀素沉积。此外，我们 在载脂蛋白E4携带者中，特别是在2型糖尿病患者中，发现脑淀粉素水平高出4倍。 提示淀粉蛋白在大脑中的积累与载脂蛋白E和代谢危险因素有关。使用老鼠 在胰腺中表达人胰淀素和敲除胰淀素后，我们发现大脑中胰淀素的积累是 可能通过与血浆低密度的相互作用促进血液中寡聚化胰淀素水平的升高 脂蛋白，并导致神经炎症和神经功能缺陷。在这里，我们建议测试这些想法。 计划中的研究将使用大鼠模型来确定大脑的生理和功能变化 人胰淀素在胰腺中的表达和适当的对照(目标1)。我们将具体地 确定治疗靶点以减少胰淀素在大脑中引起的细胞毒性。制药业 干预措施将加强机械性的洞察力，同时也提供关于 人类脑内淀粉素的蓄积和潜在的功能效应。人体研究将阐明 胰淀素-载脂蛋白和胰淀素-Aβ相互作用促进AD病理(目标2)。在这里，我们合作 与肯塔基大学AD中心合作，该中心拥有大量的大脑、血浆和 来自临床特征良好的受试者的脑脊液样本。我们还与 伦敦大学学院神经疾患皇后广场脑库和 伦敦国王学院医学研究委员会为这一项目提供了脑组织标本 来自早发性家族性AD患者(PSEN1和APP突变携带者)。这些大脑样本将 用来阐明脑内胰淀素蓄积与AD类型之间的潜在关系 斑块，即早发性家族性AD(与Aβ寡聚化增加相关)与晚发性AD (归因于AβClearance受损)。进一步阐明胰淀素-Aβ的病理生物学 通过相互作用，我们将表达“人”胰淀素的大鼠与TgF344-19 AD大鼠模型杂交。这个 该项目的成功完成提供了改进诊断和定制特定 改变/延迟/预防衰老和代谢紊乱中的脑损伤和认知衰退的治疗方法。

Abstract We propose that an early and possibly treatable contributor to the multifactorial etiology of Alzheimer's disease (AD) involves dyshomeostasis of amylin, a pancreatic hormone that crosses the blood brain barrier and has amyloidogenic properties similar to those of the β-amyloid (Aβ) peptide. This hypothesis is supported by recent work from our lab and others showing large amylin deposits in brains of AD patients. Moreover, we found >4-fold higher brain amylin level in ApoE4 carriers, particularly in patients with type-2 diabetes, suggesting a link of the accumulation of amylin in the brain with ApoE and metabolic risk factors. Using rats expressing human amylin in the pancreas and amylin knockout, we found that the brain amylin accumulation is likely promoted by elevated blood levels of oligomerized amylin via the interaction with plasma low density lipoproteins and causes neuroinflammation and neurologic deficits. Here, we propose to test these ideas. Planned studies will determine physiological and functional changes in the brain using a rat model expressing human amylin in the pancreas and appropriate controls (Aim 1). We will specifically identify therapeutic targets to reduce amylin-induced cytotoxicity in the brain. Pharmaceutical interventions will reinforce mechanistic insights while also informing on mechanisms that underlie the brain amylin accumulation and potential functional effects in humans. Human studies will elucidate amylin-APOE and amylin-Aβ interactions contributing to AD pathology (Aim 2). Here, we collaborate with the University of Kentucky AD Center, which has a large repository of brain, plasma and cerebrospinal fluid specimens from clinically well-characterized subjects. We also collaborate with the Queen Square Brain Bank for Neurological Disorders of the University College of London and Medical Research Council of King's College London which provided for this project brain specimens from early onset familial AD patients (PSEN1 and APP mutation carriers). These brain specimens will be used to elucidate a potential relationship between the brain amylin accumulation and AD-type of plaque, i.e., early onset familial AD (associated with increased Aβ oligomerization) vs. late onset AD (attributed to the impaired Aβ clearance). To further elucidate the pathobiology of amylin-Aβ interaction, we crossed the “human” amylin expressing rat with the TgF344-19 rat model of AD. The successful completion of this project offers the potential to refining diagnosis and tailoring specific therapies to modify/ delay/ prevent brain injury and cognitive decline in aging and metabolic disorders.