Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease.

TitleProtein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease.
Publication TypeJournal Article
Year of Publication2022
AuthorsJun GR, You Y, Zhu C, Meng G, Chung J, Panitch R, Hu J, Xia W, Bennett DA, Foroud TM, San Wang L-, Haines JL, Mayeux R, Pericak-Vance MA, Schellenberg GD, Au R, Lunetta KL, Ikezu T, Stein TD, Farrer LA
Corporate AuthorsAlzheimer's Disease Genetics Consortium
JournalAlzheimers Dement
Volume18
Issue11
Pagination2042-2054
Date Published11/2022
ISSN1552-5279
KeywordsAlzheimer Disease, Apolipoprotein E2, Apolipoprotein E4, Apolipoproteins E, Complement C4, Genome-Wide Association Study, Humans, Protein Phosphatase 2, tau Proteins
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 ) and the AD risk allele increased PPP2CB expression in blood (P = 6.6 × 10 ). PPP2CB expression was correlated with phosphorylated tau231/total tau ratio (P = .01) and expression of C4 protein subunits C4A/B (P = 2.0 × 10 ) in the iPSCs. PPP2CB (subunit of protein phosphatase 2A) and C4b protein levels were correlated in brain (P = 3.3 × 10 ).

DISCUSSION: PP2A may be linked to classical complement activation leading to AD-related tau pathology.
DOI10.1002/alz.12607
Alternate JournalAlzheimers Dement
PubMed ID35142023
PubMed Central IDPMC9360190
Grant ListP30 AG013854 / AG / NIA NIH HHS / United States
P50 MH060451 / MH / NIMH NIH HHS / United States
RF1 AG057768 / AG / NIA NIH HHS / United States
P30 AG072975 / AG / NIA NIH HHS / United States
R01-AG30146 / AG / NIA NIH HHS / United States
P30 AG066444 / AG / NIA NIH HHS / United States
RF1 AG054199 / AG / NIA NIH HHS / United States
R01 AG022374 / AG / NIA NIH HHS / United States
P50 AG023501 / AG / NIA NIH HHS / United States
U01 AG046152 / AG / NIA NIH HHS / United States
P30 AG010124 / AG / NIA NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
U01 AG058654 / AG / NIA NIH HHS / United States
NIMH MH60451 / NS / NINDS NIH HHS / United States
P30 AG028377 / AG / NIA NIH HHS / United States
RC2 AG036528 / AG / NIA NIH HHS / United States
RF1 AG015819 / AG / NIA NIH HHS / United States
R01 AG067763 / AG / NIA NIH HHS / United States
P50 AG008671 / AG / NIA NIH HHS / United States
R01 AG054076 / AG / NIA NIH HHS / United States
R56 AG069130 / AG / NIA NIH HHS / United States
P50 AG005142 / AG / NIA NIH HHS / United States
R01-AG15819 / AG / NIA NIH HHS / United States
R01 AG035137 / AG / NIA NIH HHS / United States
R01 AG009029 / AG / NIA NIH HHS / United States
P50 AG005131 / AG / NIA NIH HHS / United States
P50 AG005128 / AG / NIA NIH HHS / United States
P30 AG010133 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 AG031581 / AG / NIA NIH HHS / United States
R01 AG009956 / AG / NIA NIH HHS / United States
P50 AG016574 / AG / NIA NIH HHS / United States
P50 AG005146 / AG / NIA NIH HHS / United States
U01 AG061356 / AG / NIA NIH HHS / United States
R01 AG066429 / AG / NIA NIH HHS / United States
RC2 AG036650 / AG / NIA NIH HHS / United States
R01 AG019085 / AG / NIA NIH HHS / United States
U01 AG032984 / AG / NIA NIH HHS / United States
U01 HG008657 / HG / NHGRI NIH HHS / United States
R01 AG013616 / AG / NIA NIH HHS / United States
R01 AG030146 / AG / NIA NIH HHS / United States
R01 AG67763 / GF / NIH HHS / United States
R01-AG36836 / AG / NIA NIH HHS / United States
P50 AG008702 / AG / NIA NIH HHS / United States
UL1 RR029893 / RR / NCRR NIH HHS / United States
/ HHMI / Howard Hughes Medical Institute / United States
U01 AG016976 / AG / NIA NIH HHS / United States
P50 NS039764 / NS / NINDS NIH HHS / United States
P01 AG003991 / AG / NIA NIH HHS / United States
P30 AG008051 / AG / NIA NIH HHS / United States
P50 AG005681 / AG / NIA NIH HHS / United States
P30 AG013846 / AG / NIA NIH HHS / United States
RC2 AG036502 / AG / NIA NIH HHS / United States
P30 AG072978 / AG / NIA NIH HHS / United States
P01 AG026276 / AG / NIA NIH HHS / United States
U24 AG056270 / AG / NIA NIH HHS / United States
R01 AG017917 / AG / NIA NIH HHS / United States
R01 MH080295 / MH / NIMH NIH HHS / United States
U01-AG46152 / AG / NIA NIH HHS / United States
R01 AG026390 / AG / NIA NIH HHS / United States
R01 AG028786 / AG / NIA NIH HHS / United States
KL2 RR024151 / RR / NCRR NIH HHS / United States
NS39764 / NS / NINDS NIH HHS / United States
P50 AG005136 / AG / NIA NIH HHS / United States
P30 AG012300 / AG / NIA NIH HHS / United States
R01-AG17917 / AG / NIA NIH HHS / United States
P50 AG016573 / AG / NIA NIH HHS / United States
R01 AG012101 / AG / NIA NIH HHS / United States
R01 AG054672 / AG / NIA NIH HHS / United States
P50 AG016570 / AG / NIA NIH HHS / United States
/ / CIHR / Canada
P30 AG008017 / AG / NIA NIH HHS / United States
R01 AG042437 / AG / NIA NIH HHS / United States
U24 AG041689 / AG / NIA NIH HHS / United States
P01 AG019724 / AG / NIA NIH HHS / United States
R01 AG008122 / AG / NIA NIH HHS / United States
P50 AG005134 / AG / NIA NIH HHS / United States
P30 AG010161 / AG / NIA NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
R01 CA109650 / CA / NCI NIH HHS / United States
R01 AG032990 / AG / NIA NIH HHS / United States
R37 AG015473 / AG / NIA NIH HHS / United States
U24 AG026395 / AG / NIA NIH HHS / United States
U01-AG61356 / AG / NIA NIH HHS / United States
P50 AG025688 / AG / NIA NIH HHS / United States
I01 CX001038 / CX / CSRD VA / United States
R01 CA129769 / CA / NCI NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
P30 AG066509 / AG / NIA NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
U01 AG010483 / AG / NIA NIH HHS / United States
U01 AG006781 / AG / NIA NIH HHS / United States
R01 AG041797 / AG / NIA NIH HHS / United States
P50 AG005144 / AG / NIA NIH HHS / United States
U01 AG062602 / AG / NIA NIH HHS / United States
P01 AG010491 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
R01 AG048927 / AG / NIA NIH HHS / United States
R01 AG037212 / AG / NIA NIH HHS / United States
R01 AG022018 / AG / NIA NIH HHS / United States
R01 AG021547 / AG / NIA NIH HHS / United States
R01 AG041232 / AG / NIA NIH HHS / United States
R01 AG019757 / AG / NIA NIH HHS / United States
U01-AG32984 / AG / NIA NIH HHS / United States
R01 AG020688 / AG / NIA NIH HHS / United States
R01 AG030653 / AG / NIA NIH HHS / United States
P20 MD000546 / MD / NIMHD NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
R01 AG017173 / AG / NIA NIH HHS / United States
R01 AG025259 / AG / NIA NIH HHS / United States
RF1 AG057519 / AG / NIA NIH HHS / United States
P30 AG062715 / AG / NIA NIH HHS / United States
U01 HG004610 / HG / NHGRI NIH HHS / United States
/ WT_ / Wellcome Trust / United Kingdom
P30 AG010129 / AG / NIA NIH HHS / United States
P30 AG019610 / AG / NIA NIH HHS / United States
P50 AG016582 / AG / NIA NIH HHS / United States
R01 AG041718 / AG / NIA NIH HHS / United States
P30 AG028383 / AG / NIA NIH HHS / United States
R01 AG072719 / AG / NIA NIH HHS / United States
P30-AG10161 / AG / NIA NIH HHS / United States
R01 AG026916 / AG / NIA NIH HHS / United States
P50 AG033514 / AG / NIA NIH HHS / United States
R01 NS059873 / NS / NINDS NIH HHS / United States
R21 NS104609 / GF / NIH HHS / United States
U19 AG068753 / AG / NIA NIH HHS / United States
R01 AG036836 / AG / NIA NIH HHS / United States
R01 AG072719 / GF / NIH HHS / United States
R21 NS104609 / NS / NINDS NIH HHS / United States
R01 AG015819 / AG / NIA NIH HHS / United States
RF1 AG054156 / AG / NIA NIH HHS / United States