title: A lipoprotein receptor cluster IV mutant preferentially binds amyloid-β and regulates its clearance from the mouse brain.
abstract: Soluble low density lipoprotein receptor-related protein-1 (sLRP1) binds ~70% of amyloid β-peptide (Aβ) in human plasma. In Alzheimer disease (AD) and individuals with mild cognitive impairment converting to AD, plasma sLRP1 levels are reduced and sLRP1 is oxidized, which results in diminished Aβ peripheral binding and higher levels of free Aβ in plasma. Experimental studies have shown that free circulating Aβ re-enters the brain and that sLRP1 and/or its recombinant wild type cluster IV (WT-LRPIV) prevent Aβ from entering the brain. Treatment of Alzheimer APPsw(+/0) mice with WT-LRPIV has been shown to reduce brain Aβ pathology. In addition to Aβ, LRPIV binds multiple ligands. To enhance LRPIV binding for Aβ relative to other LRP1 ligands, we generated a library of LRPIV-derived fragments and full-length LRPIV variants with glycine replacing aspartic acid residues 3394, 3556, and 3674 in the calcium binding sites. Compared with WT-LRPIV, a lead LRPIV-D3674G mutant had 1.6- and 2.7-fold higher binding affinity for Aβ40 and Aβ42 in vitro, respectively, and a lower binding affinity for other LRP1 ligands (e.g. apolipoprotein E2, E3, and E4 (1.3-1.8-fold), tissue plasminogen activator (2.7-fold), matrix metalloproteinase-9 (4.1-fold), and Factor Xa (3.8-fold)). LRPIV-D3674G cleared mouse endogenous brain Aβ40 and Aβ42 25-27% better than WT-LRPIV. A 3-month subcutaneous treatment of APPsw(+/0) mice with LRPIV-D3674G (40 μg/kg/day) reduced Aβ40 and Αβ42 levels in the hippocampus, cortex, and cerebrospinal fluid by 60-80% and improved cerebral blood flow responses and hippocampal function at 9 months of age. Thus, LRPIV-D3674G is an efficient new Aβ clearance therapy.
authors.affiliation: Zilkha Neurogenetic Institute and Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Abhay P
authors.initials: AP
authors.lastname: Sagare
authors.forename: Robert D
authors.initials: RD
authors.lastname: Bell
authors.forename: Alaka
authors.initials: A
authors.lastname: Srivastava
authors.forename: Jesse D
authors.initials: JD
authors.lastname: Sengillo
authors.forename: Itender
authors.initials: I
authors.lastname: Singh
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Nishida
authors.forename: Nienwen
authors.initials: N
authors.lastname: Chow
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D019943:Amino Acid Substitution; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000235:genetics; D006224:Cricetinae; D003412:Cricetulus; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008817:Mice, Mutant Strains; D020125:Mutation, Missense; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding / Q000235:genetics; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D008024:Ligands; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D010446:Peptide Fragments; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; C075222:amyloid beta-protein (1-42)
keywords: Aging; Alzheimer Disease; Amyloid; Amyloid Precursor Protein; Amyloid-beta; Clearance Therapy; LRPIV Mutant; Lipoprotein Receptor; Neurodegenerative Diseases; sLRP1