Leptin Signaling and Alzheimer's Disease

瘦素信号传导和阿尔茨海默病

• 批准号: 8701451
• 负责人: Michael Paul Murphy
• 金额: $ 22.51万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701451
• 关键词: Adipocytes; Affect; Age; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Aneurysm; Animals; Beryllium; Biological; Biological Process; Brain; Case Mixes; Characteristics; Clinical; Complex; Data; Dementia; Dependovirus; Deposition; Development; Diabetes Mellitus; Disasters; Disease; Electron Microscopy; Employee Strikes; Endothelial Cells; Epidemiology; Etiology; Exhibits; Foundations; Functional disorder; Future; Genotype; Health; Hunger; Hypothalamic structure; Image; Impaired cognition; Individual; Injury; Knock-in Mouse; Knowledge; Leptin; Leptin resistance; Lesion; Life Style; Link; Magnetic Resonance Imaging; Mediator of activation protein; Metabolic; Metabolic Diseases; Modeling; Mus; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurologic Dysfunctions; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Phenotype; Play; Population; Predisposition; Public Health; Recording of previous events; Resistance; Risk; Risk Factors; Role; Satiation; Senile Plaques; Serum; Signal Transduction; Societies; Stroke; System; Testing; Therapeutic; Variant; Vascular Dementia; Weight; age related; aging brain; angiogenesis; cerebrovascular; cognitive function; demographics; diabetic; disease phenotype; high risk; improved; improved functioning; innovation; leptin receptor; light microscopy; middle age; mouse leptin receptor; mouse model; nervous system disorder; neuronal survival; neuropathology; novel; peptide hormone; prevent; receptor; repaired; therapeutic development

DESCRIPTION (provided by applicant): Alzheimer's disease (AD) is the most common age-related neurodegenerative disease, currently affecting more than five million people in the U.S.A. The vast majority of AD cases are sporadic, with no clear etiology. It is well-documented that lifestyle and overall health play a role in the development of the disease. A connection exists between risk for AD and Type 2 Diabetes Mellitus (T2DM), a metabolic disease that is linked to obesity. The mechanism that underlies this epidemiological connection is unknown. Recent neuropathology studies have shown that AD cases that have a history of T2DM and obesity have substantially more cerebrovascular pathology, but have either the same or lesser amounts of neuritic plaques and neurofibrillary tangles. It may be that changes in the cerebrovasculature alter the threshold for the development of AD, or that individuals with AD and a history of obesity represent cases of mixed AD and vascular dementia (VaD). This proposal considers the possibility that these elements are connected through defective leptin signaling, since individuals with a history of obesity and diabetes are leptin resistant. Leptin is an adipocyte-derived peptide hormone that regulates satiety and hunger via signaling through the leptin receptor (LepR), and these receptors are expressed throughout the brain. To explore the connection between leptin resistance, obesity and AD, we created a unique mouse line (db/AD) that combines features of these pathophysiologic states. These mice are resistant to leptin (the LepR is inactivated), become rapidly obese and diabetic, and develop AD-related neuropathology. These mice also develop a striking phenotype of cerebrovascular pathology, and display a profound cognitive impairment. In recent years, several studies have linked leptin with cognitive function. It has even been suggested that leptin treatment may be a viable therapeutic approach towards alleviating age-related cognitive decline. This project proposes to directly test the role of leptin in cognitive function in our novel model by selectively replacing he defective LepR in the brain with a functional version via adeno-associated virus, thereby restoring leptin sensitivity. Preliminary tests indicate that we are able to replace the receptor without affecting the hypothalamus, and the animals remain hyperphagic and retain their metabolic disease phenotype. We therefore believe that this approach will allow us to separate the effects of leptin on the development of neurologic dysfunction from the many complex problems associated with obesity and systemic metabolic disease. If leptin resistance is the cause of the cognitive dysfunction in the db/AD mice, then restoring leptin sensitivity will improve function. This project, utilizing a novel and innovative mouse model, has the potential to significantly advance our understanding of the association between obesity, diabetes, and dementia. If there is a clear connection between leptin, leptin resistance and neuropathology, patients may one day benefit from preventative of therapeutic strategies targeting leptin pathways.

描述（由申请人提供）：阿尔茨海默病（Alzheimer's disease， AD）是最常见的与年龄相关的神经退行性疾病，目前在美国影响超过500万人，绝大多数AD病例是散发性的，没有明确的病因。有充分的证据表明，生活方式和整体健康状况在疾病的发展中起着重要作用。2型糖尿病（T2DM）是一种与肥胖相关的代谢性疾病。这种流行病学联系背后的机制尚不清楚。最近的神经病理学研究表明，有2型糖尿病和肥胖病史的AD患者有更多的脑血管病理，但神经斑块和神经原纤维缠结的数量相同或更少。这可能是脑血管的改变改变了AD发展的阈值，或者AD和肥胖史的个体代表了AD和血管性痴呆（VaD）的混合病例。这一建议考虑了这些因素通过有缺陷的瘦素信号连接的可能性，因为有肥胖和糖尿病史的个体是瘦素抵抗者。瘦素是