Cholesterol and amyloidogenesis

描述(申请人提供)：最近的研究表明，抗体多肽水平的增加是阿尔茨海默病最早可检测到的异常之一，并可能介导一系列下游事件，导致神经元退化和认知能力下降。越来越多的临床、流行病学和实验室研究表明，胆固醇在阿尔茨海默病的发病机制中起着重要作用。这一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的酶处理，动物研究表明胆固醇水平调节抗体在大脑中的积累(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著降低。综上所述，这些研究支持这样一种假设，即阿尔茨海默病可能是一种胆固醇稳态被改变的疾病，而且胆固醇可能参与了一系列调节疾病神经病理的事件。该应用程序建议测试以下假设：1-在人类大脑中，胆固醇含量的增加通过以更具淀粉样变性的方式改变APP的处理方式，有助于淀粉样蛋白的积累。载脂蛋白E表达水平、胆固醇血症和淀粉样蛋白病理之间存在相关的交互作用。载脂蛋白E启动子的某些多态与胆固醇水平协同作用，影响载脂蛋白E表达和淀粉样蛋白堆积的程度。我们实验室的初步和最近发表的数据表明，阿尔茨海默病转基因小鼠血浆和脑中的胆固醇含量与淀粉样蛋白病理的发展速度和载脂蛋白E的表达密切相关。正如提案中相应部分所概述的那样，这些假说是可以检验的，它们的研究将促进我们对阿尔茨海默病发病机制的理解。

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.