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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

基本信息

批准号：
10376209
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
项目类别：
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/10376209
关键词：
Acids Adherence Adhesions Aging Alzheimer&apos s Disease Alzheimer&apos 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 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 brain dysfunction cerebral capillary cerebrovascular cohort comorbidity effective therapy hypoxic ischemic injury in vivo inhibitor innovation islet amyloid polypeptide mild cognitive impairment neuroinflammation novel therapeutic intervention tau Proteins tool translational study vascular cognitive impairment and dementia

项目摘要

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）是最常见的导致认知功能障碍的脑血疾病