Jenny U Johansson1, William D Brubaker1, Harold Javitz2, Andrew W Bergen1, Denise Nishita1, Abhishek Trigunaite1, Andrés Crane1, Justine Ceballos1, Diego Mastroeni3, Andrea J Tenner4, Marwan Sabbagh5, Joseph Rogers6. 1. Biosciences Division, SRI International, Menlo Park, CA, USA. 2. Education Division, SRI International, Menlo Park, CA, USA. 3. The Biodesign Institute, Arizona State University, Tempe, AZ, USA. 4. Departments of Molecular Biology and Biochemistry, Pathology, and Neurobiology and Behavior, University of California, Irvine, CA, USA. 5. Alzheimer's and Memory Disorders Division, Barrow Neurological Institute, Phoenix, AZ, USA. 6. Biosciences Division, SRI International, Menlo Park, CA, USA. Electronic address: joseph.rogers@sri.com.
Abstract
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.
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.
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