Leptin Signaling and Alzheimer's Disease

描述(申请人提供)：阿尔茨海默病(AD)是最常见的与年龄相关的神经退行性疾病，目前在美国影响着500多万人。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在疾病的发展中起到了作用。AD的风险与2型糖尿病(T2 DM)之间存在联系，T2 DM是一种与肥胖有关的代谢性疾病。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T2 DM和肥胖病史的AD患者有更多的脑血管病变，但有相同或更少数量的神经炎斑块和神经原纤维缠结。这可能是脑血管的变化改变了AD的发展阈值，或者AD患者和肥胖史代表了混合性AD和血管性痴呆(VAD)的病例。这一建议考虑了这些因素通过有缺陷的瘦素信号联系在一起的可能性，因为有肥胖和糖尿病病史的人是瘦素抵抗的。瘦素是 一种脂肪细胞衍生的多肽激素，通过瘦素受体(Lepr)发出信号来调节饱腹感和饥饿感，这些受体在大脑中表达。为了探索瘦素抵抗、肥胖和阿尔茨海默病之间的联系，我们创建了一个独特的小鼠系(db/AD)，它结合了这些病理生理状态的特征。这些小鼠对瘦素(Lepr失活)具有抵抗力，迅速变得肥胖和糖尿病，并发展出与AD相关的神经病理。这些小鼠还出现明显的脑血管病理表型，并表现出严重的认知障碍。近年来，几项研究将瘦素与认知功能联系起来。甚至有人建议，瘦素治疗可能是一种可行的治疗方法，可以缓解与年龄相关的认知能力下降。该项目建议在我们的新模型中直接测试瘦素在认知功能中的作用，通过腺相关病毒选择性地将大脑中有缺陷的Lepr替换为功能版本，从而恢复瘦素的敏感性。初步测试表明，我们能够在不影响下丘脑的情况下更换受体，动物仍保持高吞噬状态，并保留其代谢性疾病的表型。因此，我们相信，这种方法将使我们能够将瘦素在神经功能障碍发展中的作用与与肥胖和全身代谢性疾病相关的许多复杂问题分开。如果瘦素抵抗是db/AD小鼠认知功能障碍的原因，那么恢复瘦素敏感性将改善功能。该项目利用了一种新颖而创新的小鼠模型，有可能显著提高我们对肥胖、糖尿病和痴呆症之间的联系的理解。如果瘦素、瘦素抵抗和神经病理学之间存在明确的联系，那么有一天患者可能会受益于针对瘦素途径的预防性治疗策略。

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.