Differential degradation of amyloid β genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme

被引:69
作者
Morelli, L
Llovera, R
Gonzalez, SA
Affranchino, JL
Prelli, F
Frangione, B
Ghiso, J
Castaño, EM
机构
[1] Univ Buenos Aires, Fac Farm & Bioquim, Dept Quim Biol, Catedra Quim Biol Patol,CONICET,IQUIFIB, RA-1113 Buenos Aires, DF, Argentina
[2] Consejo Nacl Invest Cient & Tecn, Ctr Virol Anim, RA-1033 Buenos Aires, DF, Argentina
[3] NYU, Dept Pathol, New York, NY 10016 USA
关键词
D O I
10.1074/jbc.M300276200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Inherited amino acid substitutions at position 21, 22, or 23 of amyloid beta (Abeta) lead to presenile dementia or stroke. Insulin-degrading enzyme (IDE) can hydrolyze Abeta wild type, yet whether IDE is capable of degrading Abeta bearing pathogenic substitutions is not known. We studied the degradation of all of the published Abeta genetic variants by recombinant rat IDE (rIDE). Monomeric Abeta wild type, Flemish (A21G), Italian (E22K), and Iowa ( D23N) variants were readily degraded by rIDE with a similar efficiency. However, proteolysis of Abeta Dutch (E22Q) and Arctic (E22G) was significantly lower as compared with Abeta wild type and the rest of the mutant peptides. In the case of Abeta Dutch, inefficient proteolysis was related to a high content of beta structure as assessed by circular dichroism. All of the Abeta variants were cleaved at Glu(3)-Phe(4) and Phe(4)-Arg(5) in addition to the previously described major sites within positions 13-15 and 18-21. SDS-stable Abeta dimers were highly resistant to proteolysis by rIDE regardless of the variant, suggesting that IDE recognizes a conformation that is available for interaction only in monomeric Abeta. These results raise the possibility that upregulation of IDE may promote the clearance of soluble Abeta in hereditary forms of Abeta diseases.
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页码:23221 / 23226
页数:6
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