Restored degradation of the Alzheimer's amyloid-beta peptide by targeting amyloid formation.
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.
Crouch
Peter J
PJ
Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia. pjcrouch@unimelb.edu.au
Tew
Deborah J
DJ
Du
Tai
T
Nguyen
Diem Ngoc
DN
Caragounis
Aphrodite
A
Filiz
Gulay
G
Blake
Rachel E
RE
Trounce
Ian A
IA
Soon
Cynthia P W
CP
Laughton
Katrina
K
Perez
Keyla A
KA
Li
Qiao-Xin
QX
Cherny
Robert A
RA
Masters
Colin L
CL
Barnham
Kevin J
KJ
White
Anthony R
AR
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
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