Cholesterol and amyloidogenesis

描述（由申请人提供）：最近的研究表明，Ab肽水平的增加是阿尔茨海默病中最早可检测到的异常之一，并可能介导导致神经元变性和认知能力下降的下游事件链。越来越多的临床、流行病学和实验室研究证据表明，胆固醇在阿尔茨海默病的发病机制中起作用。这些证据包括体外研究，表明细胞胆固醇水平调节抗体的产生和APP的酶促加工，动物研究表明胆固醇水平调节大脑中的抗体积累（初步数据），以及几项观察性临床研究，表明服用降胆固醇药物的患者可能患阿尔茨海默病的患病率和发病率显着降低。总之，这些研究支持这样的假设，即阿尔茨海默病可能是一种胆固醇稳态改变的疾病，并且胆固醇可能参与调节疾病神经病理学的一系列事件。该申请提出测试以下假设：1-在人脑中，增加的胆固醇含量通过以更淀粉样蛋白生成的方式改变APP加工而有助于淀粉样蛋白积累。2-在apoE表达水平、胆固醇血症和淀粉样蛋白病理学之间存在相关的相互作用。3-某些apoE启动子多态性与影响apoE表达和淀粉样蛋白积累程度的胆固醇水平一致。我们实验室的初步和最近发表的数据表明，阿尔茨海默氏症转基因小鼠血浆和脑中的胆固醇含量与淀粉样蛋白病理学的发展速度和apoE表达密切相关。这些假设是经得起测试的建议中相应的部分概述，他们的研究将推进我们对阿尔茨海默病的发病机制的理解。

DESCRIPTION (provided by applicant): Recent studies have shown that increased levels of Ab peptides are among the earliest detectable abnormalities in Alzheimer's disease and may mediate a chain of downstream events leading to neuronal degeneration and cognitive decline. There is increasing evidence from clinical, epidemiological and laboratory studies that cholesterol plays a role in the pathogenesis of Alzheimer's disease. This body of evidence includes in vitro studies indicating that cellular cholesterol levels modulate Ab production and the enzymatic processing of APP, animal studies demonstrating that cholesterol levels modulate Ab accumulation in the brain (preliminary data) and several observational, clinical studies suggesting that the prevalence and incidence of probable Alzheimer's disease was significantly lower in patients taking cholesterol-lowering drugs. Taken together the studies support the hypothesis that Alzheimer's disease may be a disease in which cholesterol homeostasis is altered and that cholesterol may participate in a chain of events that modulate the disease neuropathology. The application proposes to test the following hypotheses: 1-that in the human brain increased cholesterol content contributes to amyloid accumulation by changing APP processing in a more amyloidogenic manner. 2-that there are correlative interactions between levels of apoE expression, cholesterolemia and amyloid pathology. 3-that certain apoE promoter polymorphisms act in concert with cholesterol levels influencing the extent of apoE expression and amyloid accumulation. Preliminary and recently published data from our laboratory suggest that cholesterol content in plasma and brain of Alzheimer's transgenic mice is strongly correlated with rate of development of amyloid pathology and with apoE expression. These hypotheses are amenable to testing as outlined in the corresponding sections of the proposal and their study will advance our understanding of the pathogenesis of Alzheimer's disease.