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

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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.