Restored degradation of the Alzheimer's amyloid-[beta] 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. [PUBLICATION ABSTRACT]