Restored degradation of the Alzheimer's amyloid-beta peptide by targeting amyloid formation
Peter J Crouch, Deborah J Tew, Tai Du, Diem Ngoc Nguyen, Aphrodite Caragounis, Gulay Filiz, Rachel E Blake, Ian A Trounce, Cynthia PW Soon, Katrina Laughton, Keyla A Perez, Qiao-Xin Li, Robert A Cherny, Colin L Masters, Kevin J Barnham, Anthony R White
JOURNAL OF NEUROCHEMISTRY | WILEY | Published : 2009
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..View full abstract
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Awarded by National Health and Medical Research Council (NHMRC)
Awarded by University of Melbourne Early Career Researcher Grant Scheme
This work was supported by the National Health and Medical Research Council (NHMRC) through Program Grant 400202 to ARW, CLM, and KJB, and the University of Melbourne Early Career Researcher Grant Scheme (Project #500144) to PJC. ARW is a NHMRC RD Wright Fellow, KJB is a NHMRC Senior Research Fellow. SRCD was carried out with the support of the Daresbury Synchrotron Radiation Source and the assistance of David Clarke. Travel for DJT to perform SRCD work was funded by the Australian Nuclear Science and Technology Organisation through the Access to Major Resource Facilities Program. Electron microscopy was performed under the expert guidance of staff from the University of Melbourne Bio21 EM Unit.