Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy
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...
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2004
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| Acceso en línea: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v279_n53_p56004_Morelli http://hdl.handle.net/20.500.12110/paper_00219258_v279_n53_p56004_Morelli |
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paper:paper_00219258_v279_n53_p56004_Morelli2023-06-08T14:43:25Z Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy 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 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. 2004 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v279_n53_p56004_Morelli http://hdl.handle.net/20.500.12110/paper_00219258_v279_n53_p56004_Morelli |
| institution |
Universidad de Buenos Aires |
| institution_str |
I-28 |
| repository_str |
R-134 |
| collection |
Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) |
| topic |
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 |
| spellingShingle |
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 Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy |
| topic_facet |
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 |
| description |
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. |
| title |
Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy |
| title_short |
Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy |
| title_full |
Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy |
| title_fullStr |
Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy |
| title_full_unstemmed |
Insulin-degrading enzyme in brain microvessels: Proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy |
| title_sort |
insulin-degrading enzyme in brain microvessels: proteolysis of amyloid β vasculotropic variants and reduced activity in cerebral amyloid angiopathy |
| publishDate |
2004 |
| url |
https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00219258_v279_n53_p56004_Morelli http://hdl.handle.net/20.500.12110/paper_00219258_v279_n53_p56004_Morelli |
| _version_ |
1768545631281872896 |