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Restored degradation of the Alzheimer’s amyloid‐β peptide by targeting amyloid formation
Author(s) -
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 QiaoXin,
Cherny Robert A.,
Masters Colin L.,
Barnham Kevin J.,
White Anthony R.
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.05870.x
Subject(s) - proteases , clioquinol , insulin degrading enzyme , chemistry , protease , proteolysis , amyloid precursor protein , biochemistry , metalloproteinase , matrix metalloproteinase , peptide , amyloid (mycology) , amyloid precursor protein secretase , alzheimer's disease , microbiology and biotechnology , enzyme , pharmacology , biology , medicine , disease , inorganic chemistry
Accumulation of neurotoxic amyloid‐β (Aβ) is central to the pathology of Alzheimer’s disease (AD). Elucidating the mechanisms of Aβ accumulation will therefore expedite the development of Aβ‐targeting AD therapeutics. We examined activity of an Aβ‐degrading protease (matrix metalloprotease 2) to investigate whether biochemical factors consistent with conditions in the AD brain contribute to Aβ accumulation by altering Aβ sensitivity to proteolytic degradation. An Aβ amino acid mutation found in familial AD, Aβ interactions with zinc (Zn), and increased Aβ hydrophobicity all strongly prevented Aβ degradation. Consistent to all of these factors is the promotion of specific Aβ 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 Aβ accumulation by preventing normal protease activity. Zn also prevented Aβ degradation by the proteases neprilysin and insulin degrading enzyme. Treating Zn‐induced Aβ 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 Aβ‐metal interactions can inhibit Aβ accumulation by restoring the catalytic potential of Aβ‐degrading proteases.