A notable cleavage: winding up with beta-amyloid.

Abstract

How the β-amyloid peptide (Aβ) is cleaved from its precursor, the amyloid precursor protein (APP), preoccupies a large portion of the community studying Alzheimer’s disease. And for good reason. The Aβ protein, the major component of the amyloid in senile plaques, represents a leading target in the quest for agents to combat Alzheimer’s disease. Its formation involves an unusual proteolytic event within a hydrophobic stretch of amino acids predicted to form an α-helix within the membrane. APP is a type I membrane-spanning protein of 770 residues that secretes its large ectodomain after at least two different types of cleavage. Based on the abundance of the cleavage products, the site most frequently cut is at residue 687, which lies within the Aβ peptide and thus precludes its formation. The activity of the responsible, but elusive, enzyme, dubbed the α-secretase, has the property of recognizing an optimal projection length from the membrane more strongly than any specific sequence determinants (1). The α-secretase cleavage occurs in a post-Golgi compartment, possibly including caveolae (2), and may be a glycosyl-phosphatidylinositol-linked aspartyl protease (3). A small percentage of APP is not cleaved at the α-secretase site, but instead is cleaved at residue 672 of APP (which becomes Asp-1 of Aβ) by an activity dubbed β-secretase, the first step in Alzheimer’s-type amyloidogenesis. Other Aβ species with an elongated or shortened N terminus are known (4). The β-secretase cleavage, once completed, sets the stage for the next cleavage by an activity referred to as γ-secretase. In what is now considered a critical event in the disease pathogenesis, the Aβ peptide is released after cleavage by the γ-secretase either between residues 40 and 41 or between residues 42 and 43. Normally, both forms of the Aβ peptide—Aβ42 and Aβ40—are present, with Aβ40 in great excess of Aβ42. The precise cleavage site of the γ-secretase, and hence the generation of the shorter or longer Aβ peptide, is widely believed to have important pathologic consequences. Compared with Aβ40, Aβ42 deposits earlier in the disease process (5) and assembles more rapidly into filaments in vitro (6). Explanations of the mechanism of Aβ42 vs. Aβ40 cleavage by the γ-secretase are problematic because the two proteolytic sites lie on opposite sides of the predicted α-helical transmembrane domain of APP.