title: Analysis of the Putative Role of CR1 in Alzheimer's Disease: Genetic Association, Expression and Function.
abstract: Chronic activation of the complement system and induced inflammation are associated with neuropathology in Alzheimer's disease (AD). Recent large genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) in the C3b/C4b receptor (CR1 or CD35) that are associated with late onset AD. Here, anti-CR1 antibodies (Abs) directed against different epitopes of the receptor, were used to localize CR1 in brain, and relative binding affinities of the CR1 ligands, C1q and C3b, were assessed by ELISA. Most Abs tested stained red blood cells in blood vessels but showed no staining in brain parenchyma. However, two monoclonal anti-CR1 Abs labeled astrocytes in all of the cases tested, and this reactivity was preabsorbed by purified recombinant human CR1. Human brain-derived astrocyte cultures were also reactive with both mAbs. The amount of astrocyte staining varied among the samples, but no consistent difference was conferred by diagnosis or the GWAS-identified SNPs rs4844609 or rs6656401. Plasma levels of soluble CR1 did not correlate with diagnosis but a slight increase was observed with rs4844609 and rs6656401 SNP. There was also a modest but statistically significant increase in relative binding activity of C1q to CR1 with the rs4844609 SNP compared to CR1 without the SNP, and of C3b to CR1 in the CR1 genotypes containing the rs6656401 SNP (also associated with the larger isoform of CR1) regardless of clinical diagnosis. These results suggest that it is unlikely that astrocyte CR1 expression levels or C1q or C3b binding activity are the cause of the GWAS identified association of CR1 variants with AD. Further careful functional studies are needed to determine if the variant-dictated number of CR1 expressed on red blood cells contributes to the role of this receptor in the progression of AD, or if another mechanism is involved.
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California, 92697, United States of America.
authors.forename: Maria I
authors.initials: MI
authors.lastname: Fonseca
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California, 92697, United States of America.
authors.forename: Shuhui
authors.initials: S
authors.lastname: Chu
authors.affiliation: Department of Neurology, University of California Irvine, Irvine, California, 92697, United States of America.|UCI Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, California, 92697, United States of America.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Pierce
authors.affiliation: SRI International, Menlo Park, California, 94025, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Brubaker
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, 63110, United States of America.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Hauhart
authors.affiliation: Banner Sun Health Research Institute, Sun City, Arizona, 85351, United States of America.|School for Mental Health and Neuroscience (MHeNS), Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, European Graduate School of Neuroscience (EURON), Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Diego
authors.initials: D
authors.lastname: Mastroeni
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California, 92697, United States of America.
authors.forename: Elizabeth V
authors.initials: EV
authors.lastname: Clarke
authors.affiliation: SRI International, Menlo Park, California, 94025, United States of America.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rogers
authors.affiliation: Division of Rheumatology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, 63110, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Atkinson
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California, 92697, United States of America.|UCI Institute for Memory Impairment and Neurological Disorders, University of California Irvine, Irvine, California, 92697, United States of America.|Department of Neurobiology and Behavior and Department of Pathology and Laboratory Science, University of California Irvine, Irvine, California, 92697, United States of America.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Tenner
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000473:pathology; D015922:Complement C1q / Q000378:metabolism; D003179:Complement C3b / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D021381:Protein Transport; D017463:Receptors, Complement 3b / Q000097:blood / Q000235:genetics* / Q000378:metabolism*
chemical_list: C509991:CR1 protein, human; D017463:Receptors, Complement 3b; D015922:Complement C1q; D003179:Complement C3b