Restored degradation of the Alzheimer's amyloid-β peptide by targeting amyloid formation

Accumulation of neurotoxic amyloid-beta (A beta) is central to the pathology of Alzheimer's disease (AD). Elucidating the mechanisms of A beta accumulation will therefore expedite the development of A beta-targeting AD therapeutics. We examined activity of an A beta-degrading protease (matrix metalloprotease 2) to investigate whether biochemical factors consistent with conditions in the AD brain contribute to A beta accumulation by altering A beta sensitivity to proteolytic degradation. An A beta amino acid mutation found in familial AD, A beta interactions with zinc (Zn), and increased A beta hydrophobicity all strongly prevented A beta degradation. Consistent to all of these factors is the promotion of specific A beta aggregates where the protease cleavage site, confirmed by mass spectrometry, is inaccessible within an amyloid structure. These data indicate decreased degradation due to amyloid formation initiates A beta accumulation by preventing normal protease activity. Zn also prevented A beta degradation by the proteases neprilysin and insulin degrading enzyme. Treating Zn-induced A beta amyloid with the metal-protein attenuating compound clioquinol reversed amyloid formation and restored the peptide's sensitivity to degradation by matrix metalloprotease 2. This provides new data indicating that therapeutic compounds designed to modulate A beta-metal interactions can inhibit A beta accumulation by restoring the catalytic potential of A beta-degrading proteases.