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

阿尔茨海默病(AD)是认知障碍的最常见原因，但脑部血液疾病 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。不是 存在有效的治疗方法，需要创新的方法。拟议的研究引入了两个概念 创新以确定新的治疗策略。首先，研究重点是脑小血管缺血 由胰淀素代谢紊乱引起的疾病(SVID)，胰淀素是一种参与中枢神经系统的内分泌激素 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。最近的经验 我们小组提出的部分发现表明，小血管的轴突变性和适应不良， 如胶质细胞增多症，与淀粉酶的血管沉积有关。我们的初步数据也显示淀粉素沉积 大脑毛细血管中的淀粉蛋白与红血球中胰淀素的积累有关。在非阿尔茨海默病大鼠的实验中，我们发现 人胰淀素(大鼠胰淀素为非淀粉样变性)的胰腺表达促进血管胰淀素 沉积导致微出血、轴突变性和晚年发病的神经功能障碍。第二, 这项研究引入了一种新的范式，即胰淀素代谢紊乱调节大脑淀粉样蛋白的组成。几个 实验室(包括我们的实验室)报告了个体大脑中存在混合淀粉蛋白-β淀粉样蛋白(Aβ)斑块 患有病理性阿尔茨海默病。为了研究胰淀素-Aβ在体内的相互作用，我们将AD大鼠与人胰淀素-A杂交。 表达大鼠。我们的初步数据表明，表达人胰淀素的AD大鼠加速了衰老 和行为改变，而遗传或药物抑制胰淀素是保护。在这里，我们 建议使用红细胞裂解液、脑脊液样本和临床数据来检验这些假设 来自MarkVCID研究，以及机制研究和以胰淀素为中心的大鼠治疗干预 胰淀素代谢紊乱相关痴呆模型。从建议的特定目标派生的数据可以直接 导致人类预防和治疗血管性认知障碍的临床翻译研究 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.