ALTERNATIVE PROCESSING AND CHARACTERISTICS OF AMYLOID PRECURSOR PROTEIN

点击翻译按钮获取中文摘要

Beta-amyloid protein (Abeta), the major constituent of the fibrils composing senile plaques and amyloid deposits in cerebral blood vessels in Alzheimer's disease (AD) and other beta-amyloid related disorders, is a degradation product of a larger precursor APP. The deposition of Abeta in cerebral vessel wall and brain parenchyma may involve a complex interaction of different cell types and various protein factors. The comprehension of the mechanisms by which Abeta is processed from its precursor and the determination of the extent to which early and mature plaque formation contribute to neuronal cell damage and disease progression remain central and important questions in the understanding of AD. Recent findings from different groups including ours, indicate the existence of different APP degradation products, one of them containing only part of the Abeta sequence (nexin II) while another possess the intact Abeta being, therefore, potentially "amyloidogenic". Interestingly, some of these fragments including Abeta and nexin II can mediate cell adhesion. We found that the tetrapeptide RHDS can mimic the behavior of RGDS, a widely distributed cell adhesion recognition signal found in many extracellular matrix proteins. We propose i) to identify the intermediate APP C-terminal fragment(s) containing Abeta by immunochemical analysis and N-terminal sequence; ii) to use this information to engineering a construct and express it in cells in order to obtain enough amounts of fragment(s) to be used in cell adhesion and enzymatic degradation/fibril formation experiments; iii) to determine the biological importance of the sequence RHDS for both nexin II and Abeta.