APP, APLPs and BACE: Substrate-enzyme interaction in a high molecular weight complex

阿尔茨海默氏病（AD）是老年人面临的一个巨大的医学问题，有400万美国人受到影响，每年的护理费用估计约为1000亿美元。目前还无法治愈，原因仍然不确定。目前，已知由三种不同基因引起的家族性AD（FAD）的共同特征是淀粉样前体蛋白（APP）的加工，导致AD中选择性沉积的可溶性淀粉样Ab肽的细胞外浓度升高。导致AD病理的因素仍然不确定。阐明这些因素将使我们更接近这种不治之症的治疗目标。我们认为APP及其配体是AD发病级联反应的重要上游因子。我们一直在积极研究APP与相互作用伙伴之间的相互作用，这导致了许多出版物，清楚地表明这些分子在APP活动中的重要性。为了正确理解APP相互作用机制在AD中的参与，我们将研究APP寡聚化的基本机制，研究APP异构体的稳定性，并分析APP配体对寡聚化和稳定性的影响。

Alzheimer's disease (AD) is a huge medical problem for the aging population, with 4 million Americans affected, and the cost of care estimated at about Dollar100 billion annually. It is presently not curable, and the causes are still uncertain. Presently, it is known that the commmon denominator in familial AD (FAD) resulting from three different genes is the processing of the amyloid precursor protein (APP), leading to an elevated extracellular concentration of soluble amyloid Ab peptide which is selectively deposited in AD. The factors that cause the pathology of AD are still uncertain. Elucidating those factors will bring us closer to a therapeutic target for this incurable disorder. We believe that APP and its ligands are key molecules being major upstream factors in the pathogenetic cascade of AD. We have been actively studying the interactions between APP an interacting partners and this has led to a number of publications that clearly demonstrate the importance of these molecules in APP activity. To properly understand the involvement of APP interacting mechanisms in AD we shall study the basic mechanism underlying the oligomerization of APP, investigate APP isoforms for their stability and analyze the influence of APP ligands on oligomerization and stability.