Abstract
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.
Footnotes
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This study was supported in part by a Grant-in-Aid for Scientific Research on Priority Areas 17025005 from The Ministry of Education, Culture, Sports, Science and Technology, Japan, and a 21st Century Center of Excellence Program grant from the Japan Society for the Promotion of Science.
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Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.
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doi:10.1124/mol.107.036913.
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ABBREVIATIONS: Aβ, amyloid β-peptide; AD, Alzheimer's disease; α2M, α2-macroglobulin; α2M*, methylamine-activated α2 macroglobulin; DM, diabetes mellitus; LRP-1, low-density lipoprotein receptor-related protein 1; LUI, liver uptake index; PBS, phosphate-buffered saline; PPARγ, peroxisome proliferator activated receptor γ; RAP, receptor-associated protein; SD, Sprague-Dawley.
- Received April 6, 2007.
- Accepted July 3, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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