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The Journal of Neuroscience, October 27, 2004, 24(43):9632-9637; doi:10.1523/JNEUROSCI.2236-04.2004

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Neurobiology of Disease
Brain Insulin Impairs Amyloid-(1-40) Clearance from the Brain

Takeshi Shiiki,¹ Sumio Ohtsuki,^2,3,4 Atsushi Kurihara,¹ Hideo Naganuma,¹ Kenji Nishimura,¹ Masanori Tachikawa,² Ken-ichi Hosoya,^4,5 and Tetsuya Terasaki^2,3,4

¹Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Company, Shinagawa-ku, Tokyo 140-8710, Japan, ²Department of Molecular Biopharmacy and Genetics, Graduate School of Pharmaceutical Sciences, and ³New Industry Creation Hatchery Center, Tohoku University, Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan, ⁴Solution-Oriented Research for Science and Technology of Japan Science and Technology Agency, Saitama 332-0012, Japan, and ⁵Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University, Sugitani, Toyama 930-0194, Japan

Cerebral amyloid- peptide (A) clearance plays a key role in determining the brain level of A; however, its mechanism remains unclear. In this study, we investigated cerebral A clearance across the blood-brain barrier (BBB) by using the Brain Efflux Index method. [¹²⁵I]A(1-40) was eliminated from rat brain to circulating blood with a half-life of 48.8 min and a half-saturation concentration of 8.15 nM. The A(1-40) elimination rate was reduced by 30.5% in 23-month-old rats compared with 7-week-old rats. The intact form of A(1-40) was detected in plasma after intracerebral administration, indicating the occurrence of efflux transport of intact A(1-40). The A(1-40) elimination rate was significantly inhibited by coadministration of 100 µg/ml insulin and 1 mM thiorphan by 44.6 and 34.0%, respectively. The level of intact [¹²⁵I]A(1-40) in the brain was increased by coadministration of insulin. Among insulin-degrading enzyme inhibitors, bacitracin inhibited the elimination rate, whereas N-ethylmaleimide and metal chelators had no effect. Receptor-associated protein, fucoidan, 3-bromo-5-t-butyl-4-hydroxy-benzylidenemalonitrile, anti-IGF-I receptor antibody, and L-tyrosine did not affect the A(1-40) elimination rate, suggesting that the relevant receptors or transporters are not likely to be involved in the clearance. In conclusion, the present study has demonstrated the involvement of a proteolytic degradation process and an insulin-sensitive process in cerebral A(1-40) clearance in the rat.

Key words: Alzheimer's disease; amyloid-(1-40); amyloid- clearance; blood-brain barrier; Brain Efflux Index method; insulin

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Received June 26, 2003; revised September 14, 2004; accepted September 14, 2004.

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