PERSONAL DE APOYO
LLOVERA Ramiro Esteban
artículos
Título:
Differential degradation of amyloid beta genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme.
Autor/es:
MORELLI L, LLOVERA R, GONZALEZ SA, AFFRANCHINO JL, PRELLI F, FRANGIONE B, GHISO J, CASTANO EM.
Revista:
JOURNAL OF BIOLOGICAL CHEMISTRY
Referencias:
Año: 2003 p. 23221 - 23226
ISSN:
0021-9258
Resumen:
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.