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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2042-2054 |
| Number of pages | 13 |
| Journal | Alzheimer's and Dementia |
| Volume | 18 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 2022 |
Keywords
- Alzheimer's disease
- C4B
- PPP2CB
- apolipoprotein E
- human induced pluripotent stem cells
- tau protein
ASJC Scopus subject areas
- Epidemiology
- Health Policy
- Developmental Neuroscience
- Clinical Neurology
- Geriatrics and Gerontology
- Cellular and Molecular Neuroscience
- Psychiatry and Mental health
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In: Alzheimer's and Dementia, Vol. 18, No. 11, 11.2022, p. 2042-2054.
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}
TY - JOUR
T1 - Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease
AU - The Alzheimer’s Disease Genetics Consortium
AU - Jun, Gyungah R.
AU - You, Yang
AU - Zhu, Congcong
AU - Meng, Gaoyuan
AU - Chung, Jaeyoon
AU - Panitch, Rebecca
AU - Hu, Junming
AU - Xia, Weiming
AU - Bennett, David A.
AU - Foroud, Tatiana M.
AU - Wang, Li San
AU - Haines, Jonathan L.
AU - Mayeux, Richard
AU - Pericak-Vance, Margaret A.
AU - Schellenberg, Gerard D.
AU - Au, Rhoda
AU - Lunetta, Kathryn L.
AU - Ikezu, Tsuneya
AU - Stein, Thor D.
AU - Farrer, Lindsay A.
N1 - Funding Information: David Bennett serves on an adjudication committee for a Takeda Pharmaceuticals clinical trial and on a Data and Safety Monitoring Board for AbbVie. He also received a SBIR grant with Origent from the National Institute on Aging and a grant from NeuroVision grant to Rush Medical Center for amyloid eye imaging. Gerard Schellenberg received an honorarium from BrightFocus. Rhoda Au is a Scientific Advisor to Signent Health and Biogen, Inc. and a paid consultant for Eisai, Inc.; Novo Nordisk; GSK, Incm; and the Davos Alzheimer's Collaborative. Tsuneya Ikezu is a paid consultant for Easi, Inc.; Millipore; Sigma; and Takeda Pharmaceuticals, and has licensing agreements with NeuroImmune AG, Millipore Sigma, and Santa Cruz Biotechnology. Lindsay Farrer received consulting fees from the Gerson Lehrman Group and Guidepoint Global. All other authors report no conflicts of interest. Funding Information: We are indebted to contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. We thank Dr. Marilyn Miller from NIA who is an ADGC member. This study was supported by the National Institute on Aging (NIA) grants 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, and R01‐AG054076. R. Au's effort was supported by grants from the Alzheimer's Drug Discovery Foundation, Alzheimer's Association, and Evidation Health. T. Ikezu's effort was supported by NIH grants R01 AG072719, R01 AG67763, and R21 NS104609), and by grants from the Cure Alzheimer's Fund, Alzheimer's Research UK, CurePSP Foundation, and Eisai, Inc. The ROSMAP study data were provided by the Rush Alzheimer's Disease Center, Rush University Medical Center. Collection of these data was supported through funding by NIA grants P30‐AG10161, R01‐AG15819, R01‐AG17917, R01‐AG30146, R01‐AG36836, U01‐AG32984, U01‐AG46152, U01‐AG61356, the Illinois Department of Public Health, and the Translational Genomics Research Institute. NIA supported this work through the following grants: ADGC, U01‐AG032984, RC2‐AG036528. Samples from the National Cell Repository for Alzheimer's Disease (NCRAD), which receives government support under a cooperative agreement grant (U24‐AG21886) awarded by the NIA, were used in this study. GWAS data used in this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer's Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24‐AG041689‐01) and the National Alzheimer's Coordinating Center (NACC) at the University of Washington (U01‐AG016976). Phenotype data for the subjects included in the GWAS were collected with support from the following grants: 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 A&T University, P20 MD000546, R01 AG28786‐01A1; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG030146, R01 AG01101, RC2 AG036650, 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; and Washington University, P50 AG005681, P01 AG03991, P01 AG026276. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Support was also from the Alzheimer's Association (LAF, IIRG‐08‐89720; MP‐V, IIRG‐05‐14147), the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program, and BrightFocus Foundation (MP‐V, A2111048). P.S.G.‐H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, The Banner Alzheimer's Foundation, The Johnnie B. Byrd Sr. Alzheimer's Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource (funding via the Medical Research Council, local NHS trusts and Newcastle University), MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council), South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England [HEFCE], Alzheimer's Research Trust [ART], BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ex‐officio Publisher Copyright: © 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
PY - 2022/11
Y1 - 2022/11
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - C4B
KW - PPP2CB
KW - apolipoprotein E
KW - human induced pluripotent stem cells
KW - tau protein
UR - http://www.scopus.com/inward/record.url?scp=85133056784&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85133056784&partnerID=8YFLogxK
U2 - 10.1002/alz.12607
DO - 10.1002/alz.12607
M3 - Article
C2 - 35142023
AN - SCOPUS:85133056784
SN - 1552-5260
VL - 18
SP - 2042
EP - 2054
JO - Alzheimer's and Dementia
JF - Alzheimer's and Dementia
IS - 11
ER -