期刊
ALZHEIMERS & DEMENTIA
卷 18, 期 11, 页码 2042-2054出版社
WILEY
DOI: 10.1002/alz.12607
关键词
Alzheimer's disease; apolipoprotein E; C4B; human induced pluripotent stem cells; PPP2CB; tau protein
资金
- NIA [P30-AG10161, R01-AG15819, R01-AG17917, R01-AG30146, R01-AG36836, U01-AG32984, U01-AG46152, U01-AG61356, U24-AG21886, AG041232]
- National Institute on Aging (NIA) [RF1-AG057519, R01-AG048927, P30-AG072978, U01-AG032984, U19-AG068753, U01-AG062602, U01-AG058654, RF1-AG054156, RF1-AG08122, RF1-AG054076, RF1-AG054199, R01-AG066429, R01-AG054672, R01-AG054076]
- Alzheimer's Drug Discovery Foundation
- Alzheimer's Association
- Evidation Health
- NIH [R01 AG072719, R01 AG67763, R21 NS104609]
- Cure Alzheimer's Fund
- Alzheimer's Research UK
- CurePSP Foundation
- Eisai, Inc.
- Illinois Department of Public Health
- Translational Genomics Research Institute
- ADGC [U01-AG032984, RC2-AG036528]
- National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania [U24-AG041689-01]
- National Alzheimer's Coordinating Center (NACC) at the University of Washington [U01-AG016976]
- NIA LOAD (Columbia University) [U24 AG026395, U24 AG026390, R01AG041797]
- Banner Sun Health Research Institute [P30 AG019610]
- Boston University [P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01 AG048927, R01AG33193, R01 AG009029]
- Columbia University [P50 AG008702, R37 AG015473, R01 AG037212, R01 AG028786]
- Duke University [P30 AG028377, AG05128]
- Emory University [AG025688]
- Group Health Research Institute [UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657]
- Indiana University [P30 AG10133, R01 AG009956, RC2 AG036650]
- Johns Hopkins University [P50 AG005146, R01 AG020688]
- Massachusetts General Hospital [P50 AG005134]
- Mayo Clinic [P50 AG016574, R01 AG032990, KL2 RR024151]
- Mount Sinai School of Medicine [P50 AG005138, P01 AG002219]
- New York University [P30 AG08051, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137]
- North Carolina AT University [P20 MD000546, R01 AG28786-01A1]
- Northwestern University [P30 AG013854]
- Oregon Health & Science University [P30 AG008017, R01 AG026916]
- Rush University [RC2 AG036650, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG030146, R01 AG01101, R01 AG22018]
- TGen [R01 NS059873]
- University of Alabama at Birmingham [P50 AG016582]
- University of Arizona [R01 AG031581]
- University of California, Davis [P30 AG010129]
- University of California, Irvine [P50 AG016573]
- University of California, Los Angeles [P50 AG016570]
- University of California, San Diego [P50 AG005131]
- University of California, San Francisco [P50 AG023501, P01 AG019724]
- University of Kentucky [P30 AG028383, AG05144]
- University of Michigan [P50 AG008671]
- University of Pennsylvania [P30 AG010124]
- University of Pittsburgh [P50 AG005133, AG030653, AG041718, AG07562, AG02365]
- University of Southern California [P50 AG005142]
- University of Texas Southwestern [P30 AG012300]
- University of Miami [R01 AG027944, AG010491, AG027944, AG021547, AG019757]
- University of Washington [P50 AG005136, R01 AG042437]
- University of Wisconsin [P50 AG033514]
- Vanderbilt University [R01 AG019085]
- Washington University [P50 AG005681, P01 AG03991, P01 AG026276]
- NINDS [NS39764]
- NIMH [MH60451]
- Glaxo Smith Kline
- US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program
- BrightFocus Foundation [A2111048]
- Wellcome Trust
- Howard Hughes Medical Institute
- Canadian Institute of Health Research
- Kronos Science
- The Banner Alzheimer's Foundation
- The Johnnie B. Byrd Sr. Alzheimer's Institute
- Medical Research Council
- state of Arizona
- NHS trusts
- Newcastle University
- Higher Education Funding Council for England [HEFCE]
- Alzheimer's Research Trust [ART]
- BRACE
- DeNDRoN
- Stichting MS Research
- Brain Net Europe
- Hersenstichting Nederland Breinbrekend Werk
- International Parkinson Fonds
- Internationale Stiching Alzheimer Onderzoek
- Alzheimer's Association [IIRG-08-89720, IIRG-05-14147]
- North Bristol NHS Trust Research and Innovation Department
This study found that the APOE e2 allele reduces the risk of developing Alzheimer's disease. The PPP2CB gene was identified as being significantly associated with AD risk, and it was found to be correlated with C4 protein expression.
Introduction The apolipoprotein E (APOE) e2 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 e2 carriers. The potential role of the top-ranked gene and complement 4 (C4) proteins, which were previously linked to AD in e2 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 e2 carriers (P = 1.1 x 10(-7)) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 x 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 x 10(-4)) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 x 10(-7)). Discussion PP2A may be linked to classical complement activation leading to AD-related tau pathology.
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