Affiliations: [a] Department of Basic Pharmaceutical Science, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA
| [b] Departments of Pharmacology & Experimental Therapeutics, Psychiatry, Boston University School of Medicine, Boston, MA, USA
Correspondence:
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Correspondence to: Dr. Wendy Wei Qiao Qiu, Departments of Pharmacology and Experimental Therapeutics and Psychiatry, Boston University Medical Campus, 72 East Concord Street, R-623D, Boston, Massachusetts 02118, USA. Tel.: +1 617 638 4336; Fax: +1 617 638 5254; E-mail: [email protected] and Dr. Amal Kaddoumi, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71201, USA. Tel.: +1 318 342 1460; Fax: +1 318 342 1737; E-mail: [email protected].
Abstract: Findings from Alzheimer’s disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-β (Aβ) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aβ serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aβ transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by siRNA knockdown of amylin receptor Ramp3. To explain this finding, amylin effect on Aβ transport proteins expressed at the BBB was evaluated. Findings indicated that cells treated with amylin induced LRP1 expression, a major receptor involved in brain Aβ efflux, in plasma membrane fraction, suggesting intracellular translocation of LRP1 from the cytoplasmic pool. Increased LRP1 in membrane fraction could explain, at least in part, the enhanced uptake and transport of Aβ across the BBB. Collectively, our findings indicated that amylin induced Aβ brain to blood clearance through amylin receptor by inducing LRP1 subcellular translocation to the plasma membrane of the BBB endothelium.
