Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures

Insulin degrading enzyme (IDE) is expressed in the brain and may play an important role there in the degradation of the amyloid beta peptide (Aβ). Our results show that cultured human cerebrovascular endothelial cells (HCECs), a primary component of the blood–brain barrier, express IDE and may respo...

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Bibliographic Details
Published in:Journal of neuroscience research 2006-05, Vol.83 (7), p.1262-1270
Main Authors: Lynch, John A., George, Ana M., Eisenhauer, Patricia B., Conn, Kelly, Gao, Wenwu, Carreras, Isabel, Wells, John M., McKee, Ann, Ullman, M. David, Fine, Richard E.
Format: Article
Language:English
Subjects:
Adolescent
Alzheimer's disease
Amyloid beta-Peptides - metabolism
Binding, Competitive - drug effects
Binding, Competitive - physiology
Blood-Brain Barrier - metabolism
Cell Line
Cell Line, Transformed
Cell Membrane - metabolism
Cell Membrane - ultrastructure
Cell Membrane Permeability - drug effects
Cell Membrane Permeability - physiology
Cell Polarity - physiology
Cerebral Amyloid Angiopathy - genetics
Cerebral Amyloid Angiopathy - metabolism
Cerebral Amyloid Angiopathy - physiopathology
Cerebral Arteries - metabolism
Cerebral Arteries - ultrastructure
cerebrovascular amyloid angiopathy
Endothelial Cells - metabolism
Endothelial Cells - ultrastructure
Enzyme Inhibitors - pharmacology
Humans
insulin
Insulin - metabolism
Insulin - pharmacology
Insulysin - metabolism
Male
peptidase
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Summary:Insulin degrading enzyme (IDE) is expressed in the brain and may play an important role there in the degradation of the amyloid beta peptide (Aβ). Our results show that cultured human cerebrovascular endothelial cells (HCECs), a primary component of the blood–brain barrier, express IDE and may respond to exposure to low levels of Aβ by upregulating its expression. When radiolabeled Aβ is introduced to the medium of cultured HCECs, it is rapidly degraded to smaller fragments. We believe that this degradation is largely the result of the action of IDE, as it can be substantially blocked by the presence of insulin in the medium, a competitive substrate of IDE. No inhibition is seen when an inhibitor of neprilysin, another protease that may degrade Aβ, is present in the medium. Our evidence suggests that the action of IDE occurs outside the cell, as inhibitors of internalization fail to affect the rate of the observed degradation. Further, our evidence suggests that degradation by IDE occurs on the plasma membrane, as much of the IDE present in HCECs was biotin‐labeled by a plasma membrane impermeable reagent. This activity seems to be polarity dependent, as measurement of Aβ degradation by each surface of differentiated HCECs shows greater degradation on the basolateral (brain‐facing) surface. Thus, IDE could be an important therapeutic target to decrease the amount of Aβ in the cerebrovasculature. © 2006 Wiley‐Liss, Inc.
ISSN:0360-4012
1097-4547
DOI:10.1002/jnr.20809