Atherogenic Induction of Neuroinflammation

描述（由申请人提供）：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，其中血管改变的炎症过程在疾病发病机制中起着重要作用。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AD的发展之间存在联系。我们提出，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性炎症可能对脑血管系统产生不利影响，导致ad相关的认知障碍。拟议的研究将检查是否有针对性地破坏信号通路，即p38 MAP激酶，它在炎症级联反应中起关键作用，可以改善高胆固醇血症诱导的AD小鼠模型中的神经血管炎症和认知障碍。实验将使用表达突变的人类淀粉样蛋白前体蛋白（APPTg）的转基因小鼠，该突变体缺乏p38 MAP激酶级联的一个关键成员，即mapk活化的蛋白激酶2（即MAPKAP K2或MK2），以验证该途径标志着动脉粥样硬化诱导神经血管和炎症变化导致ad样痴呆的假设。具体目的是确定激酶耗损和药物干预是否减少膳食胆固醇诱导的神经炎症和增加淀粉样蛋白沉积，从而改善APPTg小鼠的认知表现。这一发现将对设计针对阿尔茨海默病的神经血管炎症过程的治疗策略产生影响。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导致的动脉粥样硬化性炎症可能对脑血管系统产生不利影响，导致阿尔茨海默病（AD）相关的认知障碍。提出的研究探讨了靶向破坏（遗传或药理学）一个关键的促炎信号通路，即p38 MAP激酶，将改善AD样的大脑变化，在AD小鼠模型中伴有高胆固醇血症。这一发现将确定高胆固醇血症引起的全身免疫反应、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.