Gyungah R Jun1,2,3, Yang You4, Congcong Zhu1, Gaoyuan Meng5, Jaeyoon Chung1, Rebecca Panitch1, Junming Hu1, Weiming Xia4,5, David A Bennett6, Tatiana M Foroud7, Li-San Wang8, Jonathan L Haines9, Richard Mayeux10, Margaret A Pericak-Vance11, Gerard D Schellenberg8, Rhoda Au12,13,14, Kathryn L Lunetta3, Tsuneya Ikezu4,12,15, Thor D Stein5,16, Lindsay A Farrer1,2,3,12,14. 1. Department of Medicine (Biomedical Genetics), Boston University School of Medicine, Boston, Massachusetts, USA. 2. Department of Ophthalmology, Boston University School of Medicine, Boston, Massachusetts, USA. 3. Department of Biostatistics, Boston University School of Public Health, Boston, Massachusetts, USA. 4. Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts, USA. 5. Department of Veterans Affairs Medical Center, Bedford, Massachusetts, USA. 6. Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA. 7. Department of Medical and Molecular Genetics, Indiana University, Indianapolis, Indiana, USA. 8. Penn Neurodegeneration Genomics Center, Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. 9. Department of Population & Quantitative Health Sciences, Case Western Reserve University, Cleveland, Ohio, USA. 10. Taub Institute on Alzheimer's Disease and the Aging Brain, Gertrude H. Sergievsky Center Department of Neurology, Columbia University, New York, New York, USA. 11. John P. Hussman Institute for Human Genomics, Department of Human Genetics, and Dr. John T. Macdonald Foundation, University of Miami, Miami, Florida, USA. 12. Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, USA. 13. Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, Massachusetts, USA. 14. Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts, USA. 15. Center for Systems Neuroscience, Boston University School of Medicine, Boston, Massachusetts, USA. 16. Department of Pathology & Laboratory Medicine, Boston University School of Medicine, Boston, Massachusetts, USA.
Abstract
INTRODUCTION: The apolipoprotein E (APOE) ɛ2 allele reduces risk against Alzheimer's disease (AD) but mechanisms underlying this effect are largely unknown. METHODS: We conducted a genome-wide association study for AD among 2096 ɛ2 carriers. The potential role of the top-ranked gene and complement 4 (C4) proteins, which were previously linked to AD in ɛ2 carriers, was investigated using human isogenic APOE allele-specific induced pluripotent stem cell (iPSC)-derived neurons and astrocytes and in 224 neuropathologically examined human brains. RESULTS: PPP2CB rs117296832 was the second most significantly associated single nucleotide polymorphism among ɛ2 carriers (P = 1.1 × 10-7 ) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 × 10-27 ). PPP2CB expression was correlated with phosphorylated tau231/total tau ratio (P = .01) and expression of C4 protein subunits C4A/B (P = 2.0 × 10-4 ) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 × 10-7 ). DISCUSSION: PP2A may be linked to classical complement activation leading to AD-related tau pathology.
INTRODUCTION: The apolipoprotein E (APOE) ɛ2 allele reduces risk against Alzheimer's disease (AD) but mechanisms underlying this effect are largely unknown. METHODS: We conducted a genome-wide association study for AD among 2096 ɛ2 carriers. The potential role of the top-ranked gene and complement 4 (C4) proteins, which were previously linked to AD in ɛ2 carriers, was investigated using human isogenic APOE allele-specific induced pluripotent stem cell (iPSC)-derived neurons and astrocytes and in 224 neuropathologically examined human brains. RESULTS: PPP2CB rs117296832 was the second most significantly associated single nucleotide polymorphism among ɛ2 carriers (P = 1.1 × 10-7 ) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 × 10-27 ). PPP2CB expression was correlated with phosphorylated tau231/total tau ratio (P = .01) and expression of C4 protein subunits C4A/B (P = 2.0 × 10-4 ) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 × 10-7 ). DISCUSSION: PP2A may be linked to classical complement activation leading to AD-related tau pathology.
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