Premium
Protein phosphatase 2A and complement component 4 are linked to the protective effect of APOE ɛ2 for Alzheimer's disease
Author(s) -
Jun Gyungah R.,
You Yang,
Zhu Congcong,
Meng Gaoyuan,
Chung Jaeyoon,
Panitch Rebecca,
Hu Junming,
Xia Weiming,
Bennett David A.,
Foroud Tatiana M.,
Wang LiSan,
Haines Jonathan L.,
Mayeux Richard,
PericakVance Margaret A.,
Schellenberg Gerard D.,
Au Rhoda,
Lunetta Kathryn L.,
Ikezu Tsuneya,
Stein Thor D.,
Farrer Lindsay A.
Publication year - 2022
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.12607
Subject(s) - apolipoprotein e , protein phosphatase 2 , allele , protein subunit , biology , complement system , induced pluripotent stem cell , tau protein , alzheimer's disease , single nucleotide polymorphism , c4a , microbiology and biotechnology , gene , genetics , disease , genotype , medicine , immune system , embryonic stem cell
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.