title: Amylin Enhances Amyloid-β Peptide Brain to Blood Efflux Across the Blood-Brain Barrier.
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.
authors.affiliation: Department of Basic Pharmaceutical Science, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Loqman A
authors.initials: LA
authors.lastname: Mohamed
authors.affiliation: Departments of Pharmacology & Experimental Therapeutics, Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Haihao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Basic Pharmaceutical Science, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Youssef M
authors.initials: YM
authors.lastname: Mousa
authors.affiliation: Departments of Pharmacology & Experimental Therapeutics, Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Erming
authors.initials: E
authors.lastname: Wang
authors.affiliation: Departments of Pharmacology & Experimental Therapeutics, Psychiatry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Wei Qiao
authors.initials: WQ
authors.lastname: Qiu
authors.affiliation: Department of Basic Pharmaceutical Science, School of Pharmacy, University of Louisiana at Monroe, Monroe, LA, USA.
authors.forename: Amal
authors.initials: A
authors.lastname: Kaddoumi
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability / Q000502:physiology*; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D002491:Central Nervous System Agents / Q000008:administration & dosage; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D058228:Islet Amyloid Polypeptide / Q000378:metabolism* / Q000494:pharmacology; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D008822:Mice, Transgenic; D058287:Receptors, Islet Amyloid Polypeptide / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D002491:Central Nervous System Agents; D058228:Islet Amyloid Polypeptide; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D058287:Receptors, Islet Amyloid Polypeptide; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C105254:pramlintide
keywords: Alzheimer’s disease; LRP1; amylin; amyloid-β; blood-brain barrier