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 (ma...

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Published in:Journal of neurochemistry 2009-03, Vol.108 (5), p.1198
Main Authors: Crouch, Peter J, Tew, Deborah J, Du, Tai, Nguyen, Diem Ngoc, Caragounis, Aphrodite, Filiz, Gulay, Blake, Rachel E, Trounce, Ian A, Soon, Cynthia P W, Laughton, Katrina, Perez, Keyla A, Li, Qiao-Xin, Cherny, Robert A, Masters, Colin L, Barnham, Kevin J, White, Anthony R
Format: Article
Language:English
Subjects:
Alzheimer's disease
Amino acids
Biochemistry
Neurology
Peptides
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Summary: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]
ISSN:0022-3042
1471-4159
DOI:10.1111/j.1471-4159.2009.05870.x