TY - JOUR
T1 - Peripheral complement interactions with amyloid β peptide in Alzheimer's disease
T2 - Polymorphisms, structure, and function of complement receptor 1
AU - Johansson, Jenny U.
AU - Brubaker, William D.
AU - Javitz, Harold
AU - Bergen, Andrew W.
AU - Nishita, Denise
AU - Trigunaite, Abhishek
AU - Crane, Andrés
AU - Ceballos, Justine
AU - Mastroeni, Diego
AU - Tenner, Andrea J.
AU - Sabbagh, Marwan
AU - Rogers, Joseph
N1 - Funding Information:
Experiments on human erythrocyte A? uptake were supported by the National Institute on Aging of the National Institutes of Health under award number RO1AG07367. Experiments on human CR1 and its genetics were supported by the National Institute on Aging of the National Institutes of Health under award number RO1AG039750. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors especially thank the Arizona AD Research Center Tissue Bank, Dr. Thomas Beach, Ms. Lucia Sue, and Dr. Geidy E. Surrano for the generous provision of well-annotated human tissues used in this research. Genotypic and phenotypic data used here in GWAS analyses of AD risk were stored at the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University, funded by NIA. Associated data were provided by the NIA-funded Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center (NACC) and were stored at NCRAD and at the NIA Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania, funded by NIA. Contributors to the NIAGADS genetic analysis data included principal investigators on projects that were individually funded by NIA, other NIH institutes, private U.S. organizations, or foreign governmental or nongovernmental organizations.
Funding Information:
Experiments on human erythrocyte Aβ uptake were supported by the National Institute on Aging of the National Institutes of Health under award number RO1AG07367. Experiments on human CR1 and its genetics were supported by the National Institute on Aging of the National Institutes of Health under award number RO1AG039750. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors especially thank the Arizona AD Research Center Tissue Bank, Dr. Thomas Beach, Ms. Lucia Sue, and Dr. Geidy E. Surrano for the generous provision of well-annotated human tissues used in this research. Genotypic and phenotypic data used here in GWAS analyses of AD risk were stored at the National Cell Repository for Alzheimer's Disease (NCRAD) at Indiana University, funded by NIA. Associated data were provided by the NIA-funded Alzheimer's Disease Centers and the National Alzheimer's Coordinating Center (NACC) and were stored at NCRAD and at the NIA Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania, funded by NIA. Contributors to the NIAGADS genetic analysis data included principal investigators on projects that were individually funded by NIA, other NIH institutes, private U.S. organizations, or foreign governmental or nongovernmental organizations.
Publisher Copyright:
© 2018 the Alzheimer's Association
PY - 2018/11
Y1 - 2018/11
N2 - Introduction: Genome-wide association studies consistently show that single nucleotide polymorphisms (SNPs) in the complement receptor 1 (CR1) gene modestly but significantly alter Alzheimer's disease (AD) risk. Follow-up research has assumed that CR1 is expressed in the human brain despite a paucity of evidence for its function there. Alternatively, erythrocytes contain >80% of the body's CR1, where, in primates, it is known to bind circulating pathogens. Methods: Multidisciplinary methods were employed. Results: Conventional Western blots and quantitative polymerase chain reaction failed to detect CR1 in the human brain. Brain immunohistochemistry revealed only vascular CR1. By contrast, erythrocyte CR1 immunoreactivity was readily observed and was significantly deficient in AD, as was CR1-mediated erythrocyte capture of circulating amyloid β peptide. CR1 SNPs associated with decreased erythrocyte CR1 increased AD risk, whereas a CR1 SNP associated with increased erythrocyte CR1 decreased AD risk. Discussion: SNP effects on erythrocyte CR1 likely underlie the association of CR1 polymorphisms with AD risk.
AB - Introduction: Genome-wide association studies consistently show that single nucleotide polymorphisms (SNPs) in the complement receptor 1 (CR1) gene modestly but significantly alter Alzheimer's disease (AD) risk. Follow-up research has assumed that CR1 is expressed in the human brain despite a paucity of evidence for its function there. Alternatively, erythrocytes contain >80% of the body's CR1, where, in primates, it is known to bind circulating pathogens. Methods: Multidisciplinary methods were employed. Results: Conventional Western blots and quantitative polymerase chain reaction failed to detect CR1 in the human brain. Brain immunohistochemistry revealed only vascular CR1. By contrast, erythrocyte CR1 immunoreactivity was readily observed and was significantly deficient in AD, as was CR1-mediated erythrocyte capture of circulating amyloid β peptide. CR1 SNPs associated with decreased erythrocyte CR1 increased AD risk, whereas a CR1 SNP associated with increased erythrocyte CR1 decreased AD risk. Discussion: SNP effects on erythrocyte CR1 likely underlie the association of CR1 polymorphisms with AD risk.
KW - Amyloid β peptide
KW - CR1
KW - Clearance
KW - Complement C3b/C4b receptor 1
KW - Complement receptor 1
KW - Erythrocyte
KW - Immune adherence
KW - Red blood cell
KW - Single nucleotide polymorphism
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U2 - 10.1016/j.jalz.2018.04.003
DO - 10.1016/j.jalz.2018.04.003
M3 - Article
C2 - 29792870
AN - SCOPUS:85049838666
VL - 14
SP - 1438
EP - 1449
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
SN - 1552-5260
IS - 11
ER -
