Brain insulin impairs amyloid-beta(1-40) clearance from the brain.
Cerebral amyloid-beta peptide (Abeta) clearance plays a key role in determining the brain level of Abeta; however, its mechanism remains unclear. In this study, we investigated cerebral Abeta clearance across the blood-brain barrier (BBB) by using the Brain Efflux Index method. [125I]Abeta(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 Abeta(1-40) elimination rate was reduced by 30.5% in 23-month-old rats compared with 7-week-old rats. The intact form of Abeta(1-40) was detected in plasma after intracerebral administration, indicating the occurrence of efflux transport of intact Abeta(1-40). The Abeta(1-40) elimination rate was significantly inhibited by coadministration of 100 microg/ml insulin and 1 mm thiorphan by 44.6 and 34.0%, respectively. The level of intact [125I]Abeta(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 Abeta(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 Abeta(1-40) clearance in the rat.
Shiiki
Takeshi
T
Drug Metabolism and Pharmacokinetics Research Laboratories, Sankyo Company, Shinagawa-ku, Tokyo 140-8710, Japan. shiiki@sankyo.co.jp
Ohtsuki
Sumio
S
Kurihara
Atsushi
A
Naganuma
Hideo
H
Nishimura
Kenji
K
Tachikawa
Masanori
M
Hosoya
Ken-ichi
K
Terasaki
Tetsuya
T
D000375:Aging / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000097:blood / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D007328:Insulin / Q000502:physiology*; D007339:Insulysin / Q000378:metabolism; D007444:Inulin / Q000378:metabolism; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D015260:Neprilysin / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000097:blood / Q000378:metabolism*; D010446:Peptide Fragments / Q000097:blood / Q000378:metabolism*; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D016229:Amyloid beta-Peptides; D007328:Insulin; D007457:Iodine Radioisotopes; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D007444:Inulin; D015260:Neprilysin; D007339:Insulysin