Cellular function of the amyloid precursor like protein 1 in endocytosis and proteolytic shedding of APP

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Proteolytic cleavage in the extracellular domain of the amyloid precursor protein (APP) is a key regulatory step in the generation of the pathogenic amyloid b peptide (Ab), which is deposited in the brain of Alzheimer's disease patients. However, relatively little is known about the cellular processes that regulate APP cleavage and influence Ab generation, and their connections to disease development and progression. To explore the contributory pathways systematically, we carried out an expression cloning screen and identified several proteins that stimulate the so-called a-cleavage of APP and thus might reduce the generation of Ab. Surprisingly, one of these proteins is the amyloid precursor like protein 1 (APLP1), a homologue of APP. Using molecular and cell biological techniques the aim of this application is to characterize in detail how APLP1 influences APP processing and Ab generation. Moreover, we will analyze the cellular mechanism by which APLP1 stimulates APP shedding. The more detailed we understand the cellular mechanisms controlling Ab generation, the better it will be possible to devise strategies to therapeutically limit Ab generation for treating Alzheimer's disease. The project will be carried out in collaboration with other research groups within the priority program.