Ectodomain shedding of the amyloid precursor protein: Cellular control mechanisms and novel modifiers

Proteolytic cleavage in the ectodomain of the amyloid precursor protein (APP) is a key regulatory step in the generation of the Alzheimer's disease amyloid-β (Aβ) peptide and occurs through two different protease activities termed α-and β-secretase. Both proteases compete for APP cleavage, but have opposite effects on Aβ generation. At present, little is known about the cellular pathways that control APP α- or β-secretase cleavage a nd thus Aβ generation. To explore the contributory pathways in more detail we have recently employed an expression cloning screen and identified several activators of APP cleavage by α- or β-secretase. Among them were known activators of APP cleavage, for example protein kinase A, and novel activators, such as endophilin and the APP homolog amyloid precursor-like protein 1 (APLP1). Mechanistic analysis revealed that both endophilin and APLP1 reduce the rate of APP endocytosis and strongly increase APP cleavage by α-secretase. This review summarizes the results of the expression cloning screen in the context of recent developments in our understanding of the cellular regulation of APP α-secretase cleavage. Moreover, it highlights the particular importance of endocytic APP trafficking as a prime modulator of APP shedding.