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J. Biol. Chem., Vol. 278, Issue 26, 23221-23226, June 27, 2003

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

Laura Morelli , Ramiro Llovera , Silvia A. Gonzalez , José L. Affranchino , Frances Prelli ¶, Blas Frangione ¶, Jorge Ghiso ¶ and Eduardo M. Castaño  ||

From the Instituto de Química y Fisicoquímica Biológicas (IQUIFIB), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Cátedra de Química Biológica Patológica, Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, C1113AAD, Buenos Aires, Argentina, Centro de Virología Animal, CONICET, Serrano 665, Buenos Aires, Argentina, and ^¶Department of Pathology, New York University School of Medicine, New York, New York 10016

Inherited amino acid substitutions at position 21, 22, or 23 of amyloid (A) lead to presenile dementia or stroke. Insulin-degrading enzyme (IDE) can hydrolyze A wild type, yet whether IDE is capable of degrading A bearing pathogenic substitutions is not known. We studied the degradation of all of the published A genetic variants by recombinant rat IDE (rIDE). Monomeric A wild type, Flemish (A21G), Italian (E22K), and Iowa (D23N) variants were readily degraded by rIDE with a similar efficiency. However, proteolysis of A Dutch (E22Q) and Arctic (E22G) was significantly lower as compared with A wild type and the rest of the mutant peptides. In the case of A Dutch, inefficient proteolysis was related to a high content of structure as assessed by circular dichroism. All of the A 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 A 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 A. These results raise the possibility that upregulation of IDE may promote the clearance of soluble A in hereditary forms of A diseases.

Received for publication, January 9, 2003 , and in revised form, March 18, 2003.

^* This work was supported in part by Beca Carrillo Oñativia, Ministerio de Salud (to E. M. C. and L. M.), Agencia Nacional de Promoción Científica y Tecnologica Grant PICT98-05-04394 (to L. M. and E. M. C.), Fulbright Scholar Program fellowship (to L. M.), International Society for Neurochemistry-Committee for Aid and Education in Neurochemistry Award (to E. M. C.), and National Institutes of Health Grants AG10491, AG08721, and NS38777. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: IQUIFIB, CONICET, Cátedra de Química Biológica Patológica, Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junin 956, C1113AAD, Buenos Aires, Argentina. Tel.: 54-11-4-964-8288; Fax: 54-11-4-962-5457; E-mail: edcast{at}ffyb.uba.ar.

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