HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) All Versions of this Article: 278/26/23221    most recent M300276200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Morelli, L. Articles by Castaño, E. M. Search for Related Content PubMed PubMed Citation Articles by Morelli, L. Articles by Castaño, E. M. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				W.-Q. Zhao, P. N. Lacor, H. Chen, M. P. Lambert, M. J. Quon, G. A. Krafft, and W. L. Klein Insulin Receptor Dysfunction Impairs Cellular Clearance of Neurotoxic Oligomeric A{beta} J. Biol. Chem., July 10, 2009; 284(28): 18742 - 18753. [Abstract] [Full Text] [PDF]

				G. D. Van Vickle, C. L. Esh, I. D. Daugs, T. A. Kokjohn, W. M. Kalback, R. L. Patton, D. C. Luehrs, D. G. Walker, L.-F. Lue, T. G. Beach, et al. Tg-SwDI Transgenic Mice Exhibit Novel Alterations in A{beta}PP Processing, A{beta} Degradation, and Resilient Amyloid Angiopathy Am. J. Pathol., August 1, 2008; 173(2): 483 - 493. [Abstract] [Full Text] [PDF]

				Y. Takeuchi, K. Uetsuka, M. Murayama, F. Kikuta, A. Takashima, K. Doi, and H. Nakayama Complementary Distributions of Amyloid-{beta} and Neprilysin in the Brains of Dogs and Cats Vet. Pathol., July 1, 2008; 45(4): 455 - 466. [Abstract] [Full Text] [PDF]

				R. E. Llovera, M. de Tullio, L. G. Alonso, M. A. Leissring, S. B. Kaufman, A. E. Roher, G. de Prat Gay, L. Morelli, and E. M. Castano The Catalytic Domain of Insulin-degrading Enzyme Forms a Denaturant-resistant Complex with Amyloid {beta} Peptide: IMPLICATIONS FOR ALZHEIMER DISEASE PATHOGENESIS J. Biol. Chem., June 20, 2008; 283(25): 17039 - 17048. [Abstract] [Full Text] [PDF]

				A. Falkevall, N. Alikhani, S. Bhushan, P. F. Pavlov, K. Busch, K. A. Johnson, T. Eneqvist, L. Tjernberg, M. Ankarcrona, and E. Glaser Degradation of the Amyloid beta-Protein by the Novel Mitochondrial Peptidasome, PreP J. Biol. Chem., September 29, 2006; 281(39): 29096 - 29104. [Abstract] [Full Text] [PDF]

				P. Yan, X. Hu, H. Song, K. Yin, R. J. Bateman, J. R. Cirrito, Q. Xiao, F. F. Hsu, J. W. Turk, J. Xu, et al. Matrix Metalloproteinase-9 Degrades Amyloid-beta Fibrils in Vitro and Compact Plaques in Situ J. Biol. Chem., August 25, 2006; 281(34): 24566 - 24574. [Abstract] [Full Text] [PDF]

				Y. Tomidokoro, T. Lashley, A. Rostagno, T. A. Neubert, M. Bojsen-Moller, H. Braendgaard, G. Plant, J. Holton, B. Frangione, T. Revesz, et al. Familial Danish Dementia: CO-EXISTENCE OF DANISH AND ALZHEIMER AMYLOID SUBUNITS (ADan AND A{beta}) IN THE ABSENCE OF COMPACT PLAQUES J. Biol. Chem., November 4, 2005; 280(44): 36883 - 36894. [Abstract] [Full Text] [PDF]

				M. Yamamoto, M. Horiba, J. L. Buescher, D. Huang, H. E. Gendelman, R. M. Ransohoff, and T. Ikezu Overexpression of Monocyte Chemotactic Protein-1/CCL2 in {beta}-Amyloid Precursor Protein Transgenic Mice Show Accelerated Diffuse {beta}-Amyloid Deposition Am. J. Pathol., May 1, 2005; 166(5): 1475 - 1485. [Abstract] [Full Text] [PDF]

				L. Morelli, R. E. Llovera, I. Mathov, L.-F. Lue, B. Frangione, J. Ghiso, and E. M. Castano Insulin-degrading Enzyme in Brain Microvessels: PROTEOLYSIS OF AMYLOID {beta} VASCULOTROPIC VARIANTS AND REDUCED ACTIVITY IN CEREBRAL AMYLOID ANGIOPATHY J. Biol. Chem., December 31, 2004; 279(53): 56004 - 56013. [Abstract] [Full Text] [PDF]

				L. Zhao, B. Teter, T. Morihara, G. P. Lim, S. S. Ambegaokar, O. J. Ubeda, S. A. Frautschy, and G. M. Cole Insulin-Degrading Enzyme as a Downstream Target of Insulin Receptor Signaling Cascade: Implications for Alzheimer's Disease Intervention J. Neurosci., December 8, 2004; 24(49): 11120 - 11126. [Abstract] [Full Text] [PDF]

				J. Ghiso, M. Shayo, M. Calero, D. Ng, Y. Tomidokoro, S. Gandy, A. Rostagno, and B. Frangione Systemic Catabolism of Alzheimer's A{beta}40 and A{beta}42 J. Biol. Chem., October 29, 2004; 279(44): 45897 - 45908. [Abstract] [Full Text] [PDF]

				M. A. Leissring, A. Lu, M. M. Condron, D. B. Teplow, R. L. Stein, W. Farris, and D. J. Selkoe Kinetics of Amyloid {beta}-Protein Degradation Determined by Novel Fluorescence- and Fluorescence Polarization-based Assays J. Biol. Chem., September 26, 2003; 278(39): 37314 - 37320. [Abstract] [Full Text] [PDF]