Differential degradation of amyloid beta genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme.
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 Glu3-Phe4 and Phe4-Arg5 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.
Morelli
Laura
L
Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, C1113AAD, Buenos Aires, Argentina.
Llovera
Ramiro
R
Gonzalez
Silvia A
SA
Affranchino
Jose L
JL
Prelli
Frances
F
Frangione
Blas
B
Ghiso
Jorge
J
Castano
Eduardo M
EM
D016229:Amyloid beta-Peptides / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002543:Cerebral Hemorrhage / Q000201:enzymology / Q000473:pathology; D003704:Dementia / Q000235:genetics; D019281:Dimerization; D005192:Family Health; D014644:Genetic Variation; D006801:Humans; D007339:Insulysin / Q000378:metabolism*; D010446:Peptide Fragments / Q000032:analysis; D051381:Rats; D011994:Recombinant Proteins; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D020521:Stroke / Q000235:genetics
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D007339:Insulysin