Brain insulin impairs amyloid-β(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. [I-125]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 mug/ml insulin and 1 mM thiorphan by 44.6 and 34.0%, respectively. The level of intact [I-125]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.