Differential Degradation of Amyloid
Genetic Variants Associated with Hereditary Dementia or Stroke by Insulin-degrading Enzyme

MORELLI L; LLOVERA R; GONZALEZ S; AFFRANCHINO JL; PRELLI F; FRANGIONE B; GHISO J; CASTAÑO EM

JOURNAL OF BIOLOGICAL CHEMISTRY

AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC

Lugar: Bethesda, Maryland; Año: 2003 vol. 278 p. 23221 - 23226

0021-9258

Inherited amino acid substitutions at position 21, 22,or 23 of amyloid
(A
) lead to presenile dementia orstroke. Insulin-degrading enzyme (IDE) can hydrolyzeA
wild type, yet whether IDE is capable of degradingA
bearing pathogenic substitutions is not known. Westudied the degradation of all of the published A
geneticvariants by recombinant rat IDE (rIDE). MonomericA
wild type, Flemish (A21G), Italian (E22K), andIowa (D23N) variants were readily degraded by rIDEwith a similar efficiency. However, proteolysis of A
Dutch (E22Q) and Arctic (E22G) was significantly loweras compared with A
wild type and the rest of the mutantpeptides. In the case of A
Dutch, inefficient proteolysiswas related to a high content of
structure asassessed by circular dichroism. All of the A
variantswere cleaved at Glu3-Phe4 and Phe4-Arg5 in addition tothe previously described major sites within positions13–15 and 18–21. SDS-stable A
dimers were highly resistantto proteolysis by rIDE regardless of the variant,suggesting that IDE recognizes a conformation that isavailable for interaction only in monomeric A
. Theseresults raise the possibility that upregulation of IDEmay promote the clearance of soluble A
in hereditaryforms of A
diseases.