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-beta (A beta) pepticle and occurs
through two different protease activities termed alpha- and
beta-secretase. Both proteases compete for APP cleavage, but have
opposite effects on A beta generation. At present, little is known
about the cellular pathways that control APP alpha- or
beta-secretase cleavage and thus A beta 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 alpha- or beta-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 alpha-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 alpha-secretase cleavage. Moreover, it highlights
the particular importance of endocytic APP trafficking as a prime
modulator of APP shedding. Copyright (c) 2006 S. Karger AG, Basel.