Involvement of Insulin-Degrading Enzyme in Insulin- and Atrial Natriuretic Peptide-Sensitive Internalization of Amyloid-β Peptide in Mouse Brain Capillary Endothelial Cells

Article type: Research Article

Authors: Ito, Shingo^{a; b; c} | Ohtsuki, Sumio^{a; b; c} | Murata, Sho^a | Katsukura, Yuki^{a; b} | Suzuki, Hiroya^a | Funaki, Miho^a | Tachikawa, Masanori^a | Terasaki, Tetsuya^{a; b; *}

Affiliations: [a] Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai, Japan | [b] SORST of the Japan Science and Technology Agency, Japan | [c] Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto, Japan

Correspondence: [*] Correspondence to: Tetsuya Terasaki, Division of Membrane Transport and Drug Targeting, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. Tel.: +81 22 795 6831; Fax: +81 22 795 6886; E-mail: terasaki.tetsuya@m.tohoku.ac.jp.

Abstract: 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.

Keywords: Alzheimer's disease, amyloid-β peptide, atrial natriuretic peptide, blood-brain barrier, brain capillary endothelial cells, insulin-degrading enzyme

DOI: 10.3233/JAD-122077

Journal: Journal of Alzheimer's Disease, vol. 38, no. 1, pp. 185-200, 2014