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

阿尔茨海默病（AD）是老龄化人口的一个巨大医疗问题，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，病因也尚不清楚。目前，已知三种不同基因导致家族性AD （FAD）的共同点是淀粉样蛋白前体蛋白（APP）的加工，导致可溶性淀粉样Ab肽的细胞外浓度升高，选择性沉积在AD中。引起AD病理的因素仍不确定。阐明这些因素将使我们更接近这种无法治愈的疾病的治疗目标。我们认为APP及其配体是AD发病级联的主要上游因子的关键分子。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，清楚地证明了这些分子在APP活性中的重要性。为了更好地理解APP相互作用机制在AD中的作用，我们需要研究APP寡聚的基本机制，研究APP同工异构体的稳定性，分析APP配体对寡聚和稳定性的影响。

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.