Atherogenic Induction of Neuroinflammation

描述(申请人提供)：炎症是包括阿尔茨海默病(AD)在内的许多神经退行性疾病的共同特征，其中炎症过程与血管变化密切相关，在疾病发病机制中发挥重要作用。最近的遗传学、实验和流行病学研究结果进一步表明，高血压、糖尿病、动脉粥样硬化和高胆固醇血症等血管危险因素与阿尔茨海默病的发生有关。我们认为，由于饮食和/或遗传原因导致的胆固醇稳态失调导致的动脉粥样硬化炎症可能会对脑血管系统产生不利影响，导致AD相关的认知功能障碍。这项拟议的研究将检验靶向阻断参与炎症级联反应的信号通路，即p38 MAP激酶，是否会改善高胆固醇血症引起的神经血管炎症和AD小鼠模型的认知障碍。实验将使用表达突变的人淀粉样前体蛋白(APPTg)的转基因小鼠，该突变的人淀粉样前体蛋白(APPTg)是p38 MAP激酶级联的关键成员，即MAPK激活的蛋白激酶2(即MAPKAP K2或MK2)，以检验这一途径是否信号导致动脉粥样硬化诱导神经血管和炎性变化导致AD样痴呆。具体目标是确定在APPTg小鼠中，激酶耗竭和药物干预是否减少了饮食中胆固醇诱导的神经炎症和淀粉样蛋白沉积，从而改善了认知能力。这一发现将对设计针对阿尔茨海默病神经血管炎症过程的治疗策略具有指导意义。公共卫生相关性：由于饮食和/或遗传原因导致的胆固醇稳态失调引起的致动脉粥样硬化性炎症可能会对脑血管系统造成不利影响，从而导致阿尔茨海默病(AD)相关的认知障碍。这项拟议的研究探索了这样一种想法，即靶向阻断(遗传或药物)关键的促炎信号通路，即p38 MAP激酶，将改善高胆固醇血症小鼠模型中类似AD的脑变化。这些发现将确定高胆固醇血症诱导的系统免疫反应、大脑功能和行为之间的功能联系。

DESCRIPTION (provided by applicant): Inflammation is a common feature of a number of neurodegenerative diseases including Alzheimer's disease (AD) wherein inflammatory processes with significant contribution by vascular changes play a role in disease pathogenesis. Recent genetic, experimental and epidemiological findings further suggest a link between vascular risk factors including hypertension, diabetes, atherosclerosis and hypercholesterolemia and the development of AD. We propose that atherogenic inflammation resulting from a dysregulation of cholesterol homeostasis due to dietary and/or genetic causes may adversely affect the brain vasculature, leading to AD-associated cognitive impairment. The proposed studies will examine if targeted disruption of a signaling pathway i.e., p38 MAP kinase, that is critically involved in inflammatory cascades would ameliorate hypercholesterolemia-induced neurovascular inflammation and cognitive impairment in a mouse model of AD. The experiments will use transgenic mice expressing mutant human amyloid precursor protein (APPTg) made deficient in a key member of the p38 MAP kinase cascade i.e., MAPK-activated protein kinase 2 (i.e., MAPKAP K2 or MK2) to test the hypothesis that this pathway signals atherogenic induction of neurovascular and inflammatory changes leading to AD-like dementia. The specific objectives are to determine if the kinase depletion and pharmacological intervention reduce dietary cholesterol-induced neuroinflammation and increased amyloid deposition in the APPTg mice with the outcome of an improved cognitive performance. The findings will have implications for designing therapeutic strategies targeted towards neurovascular inflammatory processes in AD. PUBLIC HEALTH RELEVANCE: Atherogenic inflammation resulting from a dysregulation of cholesterol homeostasis due to dietary and/or genetic causes may adversely affect the brain vasculature leading to Alzheimer's disease (AD)-associated cognitive impairment. The proposed studies explore the idea that targeted disruption (genetic or pharmacological) of a key proinflammatory signaling pathway i.e., p38 MAP kinase, would ameliorate AD-like brain changes in a mouse model of AD with hypercholesterolemia. The findings would define a functional link between hypercholesterolemia-induced systemic immune response, brain function and behavior.