Insulin facilitates the hepatic clearance of plasma amyloid β-peptide (1- 40) by intracellular translocation of low-density lipoprotein receptor-related protein 1 (LRP-1) to the plasma membrane in hepatocytes

The hepatic clearance of amyloid β-peptide (1- 40) [Aβ(1- 40)] from plasma, which is largely mediated by low-density lipoprotein receptor-related protein (LRP-1), is suggested to play a role in preventing Aβ(1- 40) accumulation in the brain. Epidemiological investigations suggest a high incidence of cerebral Aβ deposition in insulin-resistant type II diabetes mellitus. The purpose of this study was to clarify the effect of insulin on the hepatic clearance of Aβ(1-40). LRP-1 expression on the hepatic plasma membrane was increased in a time-dependent manner by portal infusion of insulin and was 2.2-fold greater than that in nontreated controls after a 10-min infusion, whereas the expression in whole lysate was not affected by insulin treatment. The apparent hepatic uptake of [¹²⁵I] Aβ(1-40) was also induced by insulin in a time-dependent manner. The increase in [¹²⁵I]Aβ(1-40) uptake by insulin was concentration-dependent (EC₅₀ = 230 pM) and was completely abolished by receptor-associated protein (2 μM), an LRP-1 inhibitor. In conclusion, plasma insulin facilitates LRP-1 translocation to the hepatic plasma membrane from the intracellular pool, resulting in significant enhancement of hepatic Aβ(1-40) uptake from the circulating blood. The presently proposed mechanism would explain the epidemiological results demonstrating that type II diabetes mellitus is a risk factor of Alzheimer's disease.