The Amylin Dyshomeostasis Hypothesis of Vascular Contributions to Cognitive Impairment and Dementia (VCID)

阿尔茨海默病（Alzheimer's disease，AD）是最常见的认知功能障碍，但脑血 血管，特别是供应大脑所有细胞的小血管，也是主要的贡献者。没有 有效的疗法是存在的，需要创新的方法。研究提出了两个概念 创新，以确定新的治疗策略。首先，研究重点是脑小血管缺血 胰淀素是一种内分泌激素，参与中枢神经系统的调节， 调节饱腹感，也已知在2型糖尿病患者中形成胰腺淀粉样蛋白。最近的实证 我们小组的部分研究结果表明，轴突变性和小血管的适应不良， 如神经胶质增生与胰淀素的血管沉积有关。我们的初步数据还显示胰淀素沉积 与红细胞中胰淀素的积累相关。在非AD大鼠中，我们发现 人胰淀素（大鼠胰淀素是非淀粉样蛋白生成的）的胰腺表达促进血管胰淀素 沉积导致微血管病变、轴突变性和晚期神经功能缺损。第二、 这项研究引入了一个新的范例，即胰淀素稳态失调调节脑淀粉样蛋白的组成。几 一些实验室（包括我们的实验室）报告了在个体的大脑中存在混合的胰淀素-β淀粉样蛋白（Aβ）斑块 病理性AD为了研究胰淀素-A β在体内的相互作用，我们将AD大鼠与人胰淀素- 表达老鼠我们的初步数据表明表达人淀粉样蛋白的AD大鼠加速了衰老 和行为改变，而胰淀素的遗传或药理学抑制是保护性的。这里我们 我建议通过使用红细胞裂解物、脑脊液样本和临床数据来检验这些假设 根据MarkVCID研究，沿着机制研究和大鼠中以淀粉样蛋白为中心的治疗干预 胰淀素异位沉积相关痴呆的模型。从拟议的具体目标中得出的数据可以直接 导致预防和治疗血管性认知障碍的人类临床转化研究 和/或目前缺乏有效治疗的混合病理疾病状态。

Alzheimer's disease (AD) is the most common cause of cognitive impairment, but diseases of cerebral blood vessels, particularly the small blood vessels that supply all cells of the brain, are also major contributors. No effective therapies exist, and innovative approaches are needed. The proposed study introduces two conceptual innovations to identify novel therapeutic strategies. First, the study focuses on cerebral small vessel ischemic disease (SVID) induced by dyshomeostasis of amylin, an endocrine hormone that participates in the central regulation of satiety and also known to form pancreatic amyloid in patients with type-2 diabetes. Recent empirical findings advanced in part by our group suggest that axonal degeneration and maladaptation of small vessels, such as gliosis, are linked by vascular deposits of amylin. Our preliminary data also show that amylin deposition in brain capillaries correlates with accumulation of amylin in red blood cells. Working in non-AD rats, we showed that pancreatic expression of human amylin (rat amylin is non-amyloidogenic) promotes vascular amylin deposition leading to microhemorrhages, axonal degeneration and late-life onset neurological deficits. Second, the study introduces a new paradigm that amylin dyshomeostasis modulates brain amyloid composition. Several laboratories (including ours) report the presence of mixed amylin-β amyloid (Aβ) plaques in brains of individuals with pathological AD. To study the amylin-Aβ interaction in vivo, we crossed AD rats with human amylin- expressing rats. Our preliminary data indicate that human amylin-expressing AD rats have accelerated aging and behavioral changes, whereas genetic or pharmacological suppression of amylin is protective. Here, we propose to test these hypotheses by using red blood cell lysates, cerebrospinal fluid samples and clinical data from the MarkVCID study, along with mechanistic studies and amylin-centric therapeutic interventions in rat models of amylin dyshomeostasis-related dementia. Data derived from the proposed specific aims can directly lead to human clinical translational studies for the prevention and treatment of vascular cognitive impairment and/or mixed pathologic disease states that currently lack effective treatments.