Involvement of insulin-degrading enzyme in insulin- and atrial natriuretic peptide-sensitive internalization of amyloid-β peptide in mouse brain capillary endothelial cells.
Cerebral clearance of amyloid-β peptide (Aβ), which is implicated in Alzheimer's disease, involves elimination across the blood-brain barrier (BBB), and we previously showed that an insulin-sensitive process is involved in the case of Aβ1-40. The purpose of this study was to clarify the molecular mechanism of the insulin-sensitive Aβ1-40 elimination across mouse BBB. An in vivo cerebral microinjection study demonstrated that [125I]hAβ1-40 elimination from mouse brain was inhibited by human natriuretic peptide (hANP), and [125I]hANP elimination was inhibited by hAβ1-40, suggesting that hAβ1-40 and hANP share a common elimination process. Internalization of [125I]hAβ1-40 into cultured mouse brain capillary endothelial cells (TM-BBB4) was significantly inhibited by either insulin, hANP, other natriuretic peptides or insulin-degrading enzyme (IDE) inhibitors, but was not inhibited by phosphoramidon or thiorphan. Although we have reported the involvement of natriuretic peptide receptor C (Npr-C) in hANP internalization, cells stably expressing Npr-C internalized [125I]hANP but not [125I]hAβ1-40, suggesting that there is no direct interaction between Npr-C and hAβ1-40. IDE was detected in plasma membrane of TM-BBB4 cells, and internalization of [125I]hAβ1-40 by TM-BBB4 cells was reduced by IDE-targeted siRNAs. We conclude that elimination of hAβ1-40 from mouse brain across the BBB involves an insulin- and ANP-sensitive process, mediated by IDE expressed in brain capillary endothelial cells.
Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan SORST of the Japan Science and Technology Agency, Japan Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan.
Shingo
S
Ito
Sumio
S
Ohtsuki
Sho
S
Murata
Yuki
Y
Katsukura
Hiroya
H
Suzuki
Miho
M
Funaki
Masanori
M
Tachikawa
Tetsuya
T
Terasaki
D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000166:cytology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D007328:Insulin / Q000378:metabolism*; D007339:Insulysin / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism; D013997:Time Factors
D016229:Amyloid beta-Peptides; D007328:Insulin; D010446:Peptide Fragments; D034741:RNA, Small Interfering; C078592:amyloid beta-protein (1-40); D009320:Atrial Natriuretic Factor; D007339:Insulysin; D017461:Receptors, Atrial Natriuretic Factor; C073616:atrial natriuretic factor receptor C
Alzheimer's disease; amyloid-β peptide; atrial natriuretic peptide; blood-brain barrier; brain capillary endothelial cells; insulin-degrading enzyme