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

血管对认知障碍和痴呆 (VCID) 的影响的胰岛淀粉样蛋白平衡失调假说

• 批准号: 10604311
• 负责人: Florin Despa
• 金额: $ 76.4万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10604311
• 关键词: Acceleration; Acids; Adherence; Adhesions; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Arteries; Behavioral; Biopsy; Blood; Blood Vessels; Blood capillaries; Brain; Cardiovascular system; Carrying Capacities; Cerebral small vessel disease; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Clinical Data; Data; Dementia; Deposition; Development; Diabetes Mellitus; Disease; Disease Marker; Elderly; Endocrine; Enrollment; Enzymes; Epoxide hydrolase; Erythrocytes; Feasibility Studies; Genetic; Gliosis; Glucose; Hemoglobin; Hemorrhage; Hormone Antagonists; Hormones; Human; Hypersensitivity skin testing; Hypoxia; Hypoxic-Ischemic Brain Injury; Impaired cognition; Individual; Insulin; Ischemia; Isomerism; Laboratories; Link; Magnetic Resonance Imaging; Measures; Mediating; Mediator; Metabolic dysfunction; Microspheres; Modeling; National Institute of Neurological Disorders and Stroke; Neurologic Deficit; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pancreas; Participant; Pathologic; Pathologic Processes; Pathology; Patients; Phenotype; Prevention; Prevention strategy; Proteins; Rattus; Regulation; Reporting; Research Project Grants; Sampling; Satiation; Senile Plaques; Signal Pathway; Skin; Techniques; Testing; Therapeutic Intervention; Vascular Cognitive Impairment; Vascular Endothelial Cell; axonal degeneration; beta amyloid pathology; brain cell; brain dysfunction; cerebral capillary; cerebrovascular; clinical translation; cohort; comorbidity; effective therapy; hypoxic ischemic injury; in vivo; inhibitor; innovation; islet amyloid polypeptide; mild cognitive impairment; neuroinflammation; novel therapeutic intervention; pharmacologic; protective pathway; tau Proteins; tool; translational study; vascular cognitive impairment and dementia

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.

阿尔茨海默病（AD）是认知障碍的最常见原因，但脑血液疾病 血管，特别是供应大脑所有细胞的小血管，也是主要贡献者。 有效的治疗方法是存在的，并且需要创新的方法。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，该研究重点关注脑小血管缺血。 由胰淀素（一种参与中枢神经系统的内分泌激素）失调引起的疾病（SVID） 调节饱腹感，并且还已知在 2 型糖尿病患者中形成胰腺淀粉样蛋白。 我们小组的部分先进发现表明，轴突变性和小血管适应不良， 例如神经胶质细胞增生，与胰岛淀粉样多肽的血管沉积有关。我们的初步数据还表明，胰岛淀粉样多肽沉积。 我们在非 AD 大鼠中发现，脑毛细血管中的胰淀素与红细胞中胰岛淀粉样多肽的积累相关。 人胰岛淀粉样蛋白（大鼠胰岛淀粉样蛋白不产生淀粉样蛋白）的胰腺表达可促进血管胰岛淀粉样蛋白 沉积导致微出血、轴突变性和晚年出现的神经功能缺损。 该研究引入了胰岛淀粉样蛋白稳态失调调节大脑淀粉样蛋白组成的新范例。 实验室（包括我们的实验室）报告称，个体大脑中存在混合胰淀素-β 淀粉样蛋白 (Aβ) 斑块 为了研究体内胰淀素-Aβ 相互作用，我们将 AD 大鼠与人胰淀素-Aβ 进行杂交。 我们的初步数据表明，表达人类胰淀素的 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。 建议使用红细胞裂解物、脑脊液样本和临床数据来检验这些假设 来自 MarkVCID 研究，以及大鼠的机制研究和以胰淀素为中心的治疗干预 胰岛淀粉样蛋白稳态失调相关痴呆模型可以直接从所提出的具体目标中获得的数据。 引发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性疾病。