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: 10133172
• 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/10133172
• 关键词: Acids; Adherence; Adhesions; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-42; Amyloid beta-Protein; Arteries; Axon; Behavioral; Biopsy; Blood; Blood Vessels; Blood capillaries; Brain; Cardiovascular system; Carrying Capacities; Cerebral small vessel disease; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrovascular system; Cerebrum; Clinical; Clinical Data; Data; Dementia; Deposition; Development; Diabetes Mellitus; Disease; Disease Marker; Elderly; Endocrine; Enrollment; Enzymes; Epoxide hydrolase; Erythrocytes; Genetic; Gliosis; Glucose; Hemoglobin; Hormone Antagonists; Hormones; Human; Hypersensitivity skin testing; Hypoxia; Hypoxic-Ischemic Brain Injury; Impaired cognition; Impairment; Individual; Insulin; Isomerism; Laboratories; Lead; Link; Magnetic Resonance Imaging; Measures; Mediating; Mediator of activation protein; Metabolic dysfunction; Microspheres; Modeling; National Institute of Neurological Disorders and Stroke; Neurologic; Neurologic Deficit; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Pancreas; Participant; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Patients; Pharmacology; 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; cerebral capillary; cerebrovascular; cohort; comorbidity; effective therapy; hypoxic ischemic injury; in vivo; inhibitor/antagonist; innovation; islet amyloid polypeptide; mild cognitive impairment; neuroinflammation; novel therapeutic intervention; 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.

阿尔茨海默氏病（AD）是认知障碍的最常见原因，但脑血疾病 血管，特别是提供大脑所有细胞的小血管，也是主要因素。不 存在有效的疗法，需要创新的方法。拟议的研究介绍了两个概念 识别新型治疗策略的创新。首先，该研究重点是脑小血管缺血 氨基蛋白的dyshomeostis诱导的疾病（SVID）是一种参与中央的内分泌激素 调节饱腹感，并在2型糖尿病患者中形成胰腺淀粉样蛋白。最近的经验 我们小组部分提出的发现表明，小血管的轴突变性和不适。 例如神经胶质病，通过链淀粉的血管沉积物联系在一起。我们的初步数据还表明淀粉淀粉沉积 在脑毛细血管中，与红细胞中淀粉淀粉的积累相关。我们在非AD大鼠中工作，我们表明 人淀粉蛋白（大鼠淀粉蛋白是非淀粉样蛋白生成）的胰腺表达促进血管淀粉岩 沉积导致微生物检查，轴突变性和晚期发作神经系统缺陷。第二， 该研究介绍了一种新的范式，该范式可以调节大脑淀粉样蛋白组成。一些 实验室（包括我们的）报告了在个体大脑中存在混合的淀粉蛋白-β淀粉样蛋白（Aβ）斑块 与病理广告。为了研究体内淀粉蛋白-Aβ的相互作用，我们用人淀粉素跨越了AD大鼠 表达老鼠。我们的初步数据表明，表达人淀粉蛋白的AD大鼠已加速衰老 和行为的变化，而遗传或药物抑制淀粉岩受到保护。在这里，我们 提案通过使用红细胞裂解物，脑脊液样品和临床数据来检验这些假设 从MarkVCID研究中，以及机械研究和以淀粉蛋白为中心的治疗干预措施 淀粉蛋白异瘤相关痴呆的模型。从提出的特定目标得出的数据可以直接 导致人类的临床翻译研究，以预防和治疗血管认知障碍 和/或混合病理性疾病状态，目前缺乏有效治疗。