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Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-CSF barrier: Consequences of lead exposure

BACKGROUND: Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid (Aβ) peptides in the brain extracellular matrix, resulting in pathological changes and neurobehavioral deficits. Previous work from this laboratory demonstrated that the choroid plexus (CP) possesses the cap...

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Autores principales: Behl, Mamta, Zhang, Yanshu, Zheng, Wei
Formato: Texto
Lenguaje:English
Publicado: BioMed Central 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753621/
https://www.ncbi.nlm.nih.gov/pubmed/19747378
http://dx.doi.org/10.1186/1743-8454-6-11
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author Behl, Mamta
Zhang, Yanshu
Zheng, Wei
author_facet Behl, Mamta
Zhang, Yanshu
Zheng, Wei
author_sort Behl, Mamta
collection PubMed
description BACKGROUND: Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid (Aβ) peptides in the brain extracellular matrix, resulting in pathological changes and neurobehavioral deficits. Previous work from this laboratory demonstrated that the choroid plexus (CP) possesses the capacity to remove Aβ from the cerebrospinal fluid (CSF), and exposure to lead (Pb) compromises this function. Since metalloendopeptidase insulin-degrading enzyme (IDE), has been implicated in the metabolism of Aβ, we sought to investigate whether accumulation of Aβ following Pb exposure was due to the effect of Pb on IDE. METHODS: Rats were injected with a single dose of Pb acetate or an equivalent concentration of Na-acetate; CP tissues were processed to detect the location of IDE by immunohistochemistry. For in vitro studies, choroidal epithelial Z310 cells were treated with Pb for 24 h in the presence or absence of a known IDE inhibitor, N-ethylmaleimide (NEM) to assess IDE enzymatic activity and subsequent metabolic clearance of Aβ. Additionally, the expression of IDE mRNA and protein were determined using real time PCR and western blots respectively. RESULTS: Immunohistochemistry and confocal imaging revealed the presence of IDE towards the apical surface of the CP tissue with no visible alteration in either its intensity or location following Pb exposure. There was no significant difference in the expressions of either IDE mRNA or protein following Pb exposure compared to controls either in CP tissues or in Z310 cells. However, our findings revealed a significant decrease in the IDE activity following Pb exposure; this inhibition was similar to that seen in the cells treated with NEM alone. Interestingly, treatment with Pb or NEM alone significantly increased the levels of intracellular Aβ, and a greater accumulation of Aβ was seen when the cells were exposed to a combination of both. CONCLUSION: These data suggest that Pb exposure inhibits IDE activity but does not affect its expression in the CP. This, in turn, leads to a disrupted metabolism of Aβ resulting in its accumulation at the blood-CSF barrier.
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spelling pubmed-27536212009-09-29 Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-CSF barrier: Consequences of lead exposure Behl, Mamta Zhang, Yanshu Zheng, Wei Cerebrospinal Fluid Res Research BACKGROUND: Alzheimer's disease (AD) is characterized by the deposition of beta-amyloid (Aβ) peptides in the brain extracellular matrix, resulting in pathological changes and neurobehavioral deficits. Previous work from this laboratory demonstrated that the choroid plexus (CP) possesses the capacity to remove Aβ from the cerebrospinal fluid (CSF), and exposure to lead (Pb) compromises this function. Since metalloendopeptidase insulin-degrading enzyme (IDE), has been implicated in the metabolism of Aβ, we sought to investigate whether accumulation of Aβ following Pb exposure was due to the effect of Pb on IDE. METHODS: Rats were injected with a single dose of Pb acetate or an equivalent concentration of Na-acetate; CP tissues were processed to detect the location of IDE by immunohistochemistry. For in vitro studies, choroidal epithelial Z310 cells were treated with Pb for 24 h in the presence or absence of a known IDE inhibitor, N-ethylmaleimide (NEM) to assess IDE enzymatic activity and subsequent metabolic clearance of Aβ. Additionally, the expression of IDE mRNA and protein were determined using real time PCR and western blots respectively. RESULTS: Immunohistochemistry and confocal imaging revealed the presence of IDE towards the apical surface of the CP tissue with no visible alteration in either its intensity or location following Pb exposure. There was no significant difference in the expressions of either IDE mRNA or protein following Pb exposure compared to controls either in CP tissues or in Z310 cells. However, our findings revealed a significant decrease in the IDE activity following Pb exposure; this inhibition was similar to that seen in the cells treated with NEM alone. Interestingly, treatment with Pb or NEM alone significantly increased the levels of intracellular Aβ, and a greater accumulation of Aβ was seen when the cells were exposed to a combination of both. CONCLUSION: These data suggest that Pb exposure inhibits IDE activity but does not affect its expression in the CP. This, in turn, leads to a disrupted metabolism of Aβ resulting in its accumulation at the blood-CSF barrier. BioMed Central 2009-09-11 /pmc/articles/PMC2753621/ /pubmed/19747378 http://dx.doi.org/10.1186/1743-8454-6-11 Text en Copyright © 2009 Behl et al; licensee BioMed Central Ltd. http://creativecommons.org/licenses/by/2.0 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( (http://creativecommons.org/licenses/by/2.0) ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research
Behl, Mamta
Zhang, Yanshu
Zheng, Wei
Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-CSF barrier: Consequences of lead exposure
title Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-CSF barrier: Consequences of lead exposure
title_full Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-CSF barrier: Consequences of lead exposure
title_fullStr Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-CSF barrier: Consequences of lead exposure
title_full_unstemmed Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-CSF barrier: Consequences of lead exposure
title_short Involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-CSF barrier: Consequences of lead exposure
title_sort involvement of insulin-degrading enzyme in the clearance of beta-amyloid at the blood-csf barrier: consequences of lead exposure
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753621/
https://www.ncbi.nlm.nih.gov/pubmed/19747378
http://dx.doi.org/10.1186/1743-8454-6-11
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