Deciphering the genesis and fate of amyloid β-protein yields novel therapies for Alzheimer disease

The biogenesis of AβWhen APP was first cloned, the 40-and 42-residue Aβ peptides were found to comprise the last 28 amino acids of its large, N-terminal ectodomain plus the first 12 or 14 residues of its single transmembrane (TM) domain (Figure 1).This location predicted that the proteolytic cleavage creating the C-terminus of Aβ required some previous disruption of the membrane to allow access by the responsible protease (dubbed γ-secretase) into the phospholipid bilayer.It was therefore widely assumed that Aβ production was not a primary event in AD but rather followed neuronal membrane injury.The subsequent discovery that both Aβ1-40 and Aβ1-42 peptides are constitutive products of cellular metabolism and occur in normal biological fluids throughout life disproved this notion (reviewed in ref.3).The normal scission of APP near the middle of its TM domain to create Aβ provided an initial example of the mechanism that came to be recognized as regulated intramembrane proteolysis (4).The unusual protease that effects this cleavage will be discussed below.APP is a type 1 membrane glycoprotein that undergoes N-and O-linked glycosylation during its trafficking through the secretory pathway.At steady state, a small subset of APP molecules is found on the plasma membrane, and these can undergo ectodomain shedding by a proteolytic activity called α-secretase (Figure 1).The disintegrin metalloproteinases ADAM 10 and ADAM 17 can serve as α-secretases for APP (5,6).The 83-residue C-terminal fragment (C83) retained in the membrane can then undergo constitutive cleavage by γ-secretase to release the p3 peptide (residues 17-40/42