title: Restored degradation of the Alzheimer's amyloid-beta peptide by targeting amyloid formation.
abstract: Accumulation of neurotoxic amyloid-beta (Abeta) is central to the pathology of Alzheimer's disease (AD). Elucidating the mechanisms of Abeta accumulation will therefore expedite the development of Abeta-targeting AD therapeutics. We examined activity of an Abeta-degrading protease (matrix metalloprotease 2) to investigate whether biochemical factors consistent with conditions in the AD brain contribute to Abeta accumulation by altering Abeta sensitivity to proteolytic degradation. An Abeta amino acid mutation found in familial AD, Abeta interactions with zinc (Zn), and increased Abeta hydrophobicity all strongly prevented Abeta degradation. Consistent to all of these factors is the promotion of specific Abeta 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 Abeta accumulation by preventing normal protease activity. Zn also prevented Abeta degradation by the proteases neprilysin and insulin degrading enzyme. Treating Zn-induced Abeta 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 Abeta-metal interactions can inhibit Abeta accumulation by restoring the catalytic potential of Abeta-degrading proteases.
authors.affiliation: Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. pjcrouch@unimelb.edu.au
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.forename: Deborah J
authors.initials: DJ
authors.lastname: Tew
authors.forename: Tai
authors.initials: T
authors.lastname: Du
authors.forename: Diem Ngoc
authors.initials: DN
authors.lastname: Nguyen
authors.forename: Aphrodite
authors.initials: A
authors.lastname: Caragounis
authors.forename: Gulay
authors.initials: G
authors.lastname: Filiz
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Blake
authors.forename: Ian A
authors.initials: IA
authors.lastname: Trounce
authors.forename: Cynthia P W
authors.initials: CP
authors.lastname: Soon
authors.forename: Katrina
authors.initials: K
authors.lastname: Laughton
authors.forename: Keyla A
authors.initials: KA
authors.lastname: Perez
authors.forename: Qiao-Xin
authors.initials: QX
authors.lastname: Li
authors.forename: Robert A
authors.initials: RA
authors.lastname: Cherny
authors.forename: Colin L
authors.initials: CL
authors.lastname: Masters
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Barnham
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
mesh_terms: D000682:Amyloid / Q000187:drug effects / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D007464:Clioquinol / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D018698:Glutamic Acid / Q000235:genetics; D005973:Glutamine / Q000235:genetics; D006801:Humans; D007339:Insulysin / Q000494:pharmacology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation; D015260:Neprilysin / Q000494:pharmacology; D010446:Peptide Fragments / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D013997:Time Factors; D015032:Zinc / Q000494:pharmacology
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D005973:Glutamine; D018698:Glutamic Acid; D007464:Clioquinol; D015260:Neprilysin; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D007339:Insulysin; D015032:Zinc