Inhibitory Effect of Insulin-Degrading Enzyme-Selective Inhibitor, Ii1, on the Elimination of Amyloid-<i>β</i>(1-40) from Rat Brain

Amyloid-β peptide (Aβ) is eliminated from the brain across the blood-brain barrier (BBB) by an insulin-sensitive process. To investigate the involvement of insulin-degrading enzyme (IDE) in this process, the present study was implemented to clarify the effect of a novel IDE-specific inhibitor, Ii1, on the elimination of [¹²⁵I]Aβ(1-40) from rat brain via the brain efflux index method. The results showed that such elimination was significantly inhibited by the co-administration of Ii1. The maximum inhibitory effect of Ii1 and IC₅₀ were 69.4% and 9.96 µM, respectively. Insulin alone inhibited the elimination of [¹²⁵I]Aβ(1-40), but the inhibitory effect of co-administering insulin and Ii1 was not significantly different from that of Ii1 alone. Meanwhile, thiorphan, an inhibitor of neprilysin, showed an additive inhibitory effect with Ii1. Aβ(1-13) and Aβ(1-14), which are major fragments produced by the degradation of Aβ(1-40) by IDE, and inhibitors of receptor for advanced glycation end products (RAGE) did not significantly inhibit the [¹²⁵I]Aβ(1-40) elimination. These results suggest that IDE is involved in the insulin-sensitive process of [¹²⁵I]Aβ(1-40) elimination across the BBB, to which neprilysin and RAGE make minor contributions. These findings suggest that impairment of IDE may be involved in the onset of sporadic Alzheimer's disease.