Abstract:
The accumulation of amyloid α (Aβ) in the walls of small vessels in the cerebral cortex is associated with diseases characterized by dementia or stroke. These include Alzheimer's disease, Down syndrome, and sporadic and hereditary cerebral amyloid angiopathies (CAAs) related to mutations within the Aβ sequence. A higher tendency of Aβ to aggregate, a defective clearance to the systemic circulation, and insufficient proteolytic removal have been proposed as mechanisms that lead to Aβ accumulation in the brain. By using immuno-precipitation and mass spectrometry, we show that insulin-degrading enzyme (IDE) from isolated human brain microvessels was capable of degrading 125I-insulin and cleaved Aβ-(1-40) wild type and the genetic variants Aβ A21G (Flemish), Aβ E22Q (Dutch), and Aβ E22K (Italian) at the predicted sites. In microvessels from Alzheimer's disease cases with CAA, IDE protein levels showed a 44% increase as determined by sandwich enzyme-linked immunosorbent assay and Western blot. However, the activity of IDE upon radiolabeled insulin was significantly reduced in CAA as compared with age-matched controls. These results support the notion that a defect in Aβ proteolysis by IDE contributes to the accumulation of this peptide in the cortical microvasculature. Moreover they raise the possibility that IDE inhibition or inactivation is a pathogenic mechanism that may open novel strategies for the treatment of cerebrovascular Aβ amyloidoses.
Registro:
Documento: |
Artículo
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Título: | Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy |
Autor: | Morelli, L.; Llovera, R.E.; Mathov, I.; Lue, L.-F.; Frangione, B.; Ghiso, J.; Castaño, E.M. |
Filiación: | Inst. de Quim. y Fisicoquimica Biol., Departamento de Quimica Biologica, Universidad de Buenos Aires, Junin 956, C1113AAD, Buenos Aires, Argentina Sun Health Research Institute, Sun City, AZ 85351, United States Department of Pathology, New York Univ. School of Medicine, New York, NY 10016, United States
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Palabras clave: | Bioassay; Blood vessels; Brain; Diseases; Immunology; Insulin; Mass spectrometry; Precipitation (chemical); Alzheimer's disease; Brain microvessels; Cerebral amyloid angiopathy (CAA); Proteolysis; Enzymes; amyloid beta protein; insulin; iodine 125; Alzheimer disease; amino acid sequence; article; brain microcirculation; controlled study; Down syndrome; enzyme activity; enzyme inactivation; enzyme inhibition; enzyme linked immunosorbent assay; genetic variability; human; human tissue; immunoprecipitation; isotope labeling; mass spectrometry; mutation; nonhuman; priority journal; protein degradation; race difference; rat; stroke; vascular amyloidosis; Western blotting; Adult; Amyloid beta-Protein; Animals; Blotting, Western; Brain; Cerebral Amyloid Angiopathy; DNA, Complementary; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Humans; Immunohistochemistry; Immunoprecipitation; Insulin; Insulysin; Kinetics; Mass Spectrometry; Microcirculation; Microscopy, Fluorescence; Middle Aged; Mutation; Peptides; Protein Binding; Rats; Recombinant Proteins; Time Factors; Leuciscus idus |
Año: | 2004
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Volumen: | 279
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Número: | 53
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Página de inicio: | 56004
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Página de fin: | 56013
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DOI: |
http://dx.doi.org/10.1074/jbc.M407283200 |
Título revista: | Journal of Biological Chemistry
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Título revista abreviado: | J. Biol. Chem.
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ISSN: | 00219258
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CODEN: | JBCHA
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CAS: | amyloid beta protein, 109770-29-8; insulin, 9004-10-8; iodine 125, 14158-31-7, 22822-81-7; Amyloid beta-Protein; DNA, Complementary; Insulin, 11061-68-0; Insulysin, EC 3.4.24.56; Peptides; Recombinant Proteins
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Registro: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v279_n53_p56004_Morelli |
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Citas:
---------- APA ----------
Morelli, L., Llovera, R.E., Mathov, I., Lue, L.-F., Frangione, B., Ghiso, J. & Castaño, E.M.
(2004)
. Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy. Journal of Biological Chemistry, 279(53), 56004-56013.
http://dx.doi.org/10.1074/jbc.M407283200---------- CHICAGO ----------
Morelli, L., Llovera, R.E., Mathov, I., Lue, L.-F., Frangione, B., Ghiso, J., et al.
"Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy"
. Journal of Biological Chemistry 279, no. 53
(2004) : 56004-56013.
http://dx.doi.org/10.1074/jbc.M407283200---------- MLA ----------
Morelli, L., Llovera, R.E., Mathov, I., Lue, L.-F., Frangione, B., Ghiso, J., et al.
"Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy"
. Journal of Biological Chemistry, vol. 279, no. 53, 2004, pp. 56004-56013.
http://dx.doi.org/10.1074/jbc.M407283200---------- VANCOUVER ----------
Morelli, L., Llovera, R.E., Mathov, I., Lue, L.-F., Frangione, B., Ghiso, J., et al. Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy. J. Biol. Chem. 2004;279(53):56004-56013.
http://dx.doi.org/10.1074/jbc.M407283200