Protein phosphatase 2A, complement component 4, and APOE genotype linked to Alzheimer’s disease using a systems biology approach

Abstract

BackgroundRecent reports suggest that the rare apolipoprotein E (APOE) Christchurch mutation and ε2 allele protect against Alzheimer’s disease (AD) pathology by reducing the burden of tau pathology. However, the mechanism(s) underlying the ε2 protective effect linking to tau is largely unknown.MethodsThe role of the ε2 allele in Alzheimer’s disease (AD) was investigated a genome-wide association study (GWAS) for AD among 2,120 ε2 carriers from the Alzheimer Disease Genetics Consortium (ADGC), and then prioritized by gene network analysis, differential gene expression analysis at tissue- and cell-levels as well as methylation profiling of CpG sites, in prefrontal cortex tissue from 761 brains of the Religious Orders Study and Memory and Aging Project (ROSMAP) and the Framingham Heart Study (FHS), Boston University Alzheimer’s Disease Center (BUADC). The levels of two catalytic subunit proteins from protein phosphatase 2A (PPP2CA and PPP2CB) were validated in prefrontal cortex area of 193 of the FHS/BUADC brains. The findings from human autopsied brains were further validated by a co-culture experiment of human isogenic APOE induced pluripotent stem cell (iPSC) derived neurons and astrocytes.ResultsOf the significantly associated loci with AD among APOE ε2 carriers (P<10−6), PPP2CB (P=1.1×10−7) was the key node in the APOE ε2-related gene network and contained the most significant CpG site (P=7.3×10−4) located 2,814 base pair upstream of the top-ranked GWAS variant. Among APOE ε3/ε4 subjects, the level of Aβ42 was negatively correlated with protein levels of PPP2CA (P=9.9×10−3) and PPP2CB (P=2.4×10−3), and PPP2CA level was correlated with the level of pTau231 level (P=5.3×10−3). Significant correlations were also observed for PPP2CB with complement 4B (C4B) protein levels (P=3.3×10−7) and PPP2CA with cross reactive protein (CRP) levels (P=6.4×10−4). C1q level was not associated with Aβ42, pTau231, PPP2CB, or C4B levels. We confirmed the significant correlation of PPP2CB expression with pTau231/tTau ratio (P=0.01) and C4A/B (P=2.0×10−4) expression observed in brain tissue in a co-culture experiment of iPSC derived neurons and astrocytes.ConclusionWe demonstrated for the first time a molecular link between a tau phosphatase and the classical complement pathway, especially C4, and AD-related tau pathology.

Lack of ApoE inhibits ADan amyloidosis in a mouse model of familial Danish dementia

“…Total RNA-seq studies from brains of AD individuals showed the involvement of the classical complement pathway (CCP) and the phosphorylation of tau to be associated with AD in an APOE genotype-specific manner ( 36 , 37 ). Molecular profiling of the Tg-FDD +/− /ApoE −/− model revealed changes in autophagy, activated microglia, angiogenesis, and vesicle trafficking pathways, with C1q, the first subcomponent of the C1 complex of the CCP of complement activation, as one of the most upregulated genes and Ppp2r5c (the protein phosphatase 2 (PP2) regulatory subunit B'gamma), involved in the dephosphorylation of Tau, as one of the most downregulated genes.…”

Genome‐wide association and multi‐omics studies identify MGMT as a novel risk gene for Alzheimer's disease among women

“…Data for AD‐related neuropathologic traits were obtained from the same source and included Aβ and phosphorylated tau (p‐tau) measured by immunohistochemistry and neurofibrillary tangles (NFT) measured by microscopic examination as described elsewhere (http://www.radc.rush.edu). 13 We also evaluated gene expression data and semi‐quantitative measures of tau pathology (Braak stage) and neuritic amyloid plaques derived from dorsolateral prefrontal cortex tissue obtained from 177 participants (58 autopsy‐confirmed AD cases and 119 controls) of the Framingham Heart Study (FHS) 14,15 . Sample sizes for analyses of each type of omics data are presented in Tables S2 and S3 in supporting information for the ROSMAP and FHS datasets, respectively.…”

“…Hutterite cohort 13 We also evaluated gene expression data and semi-quantitative measures of tau pathology (Braak stage) and neuritic amyloid plaques derived from dorsolateral prefrontal cortex tissue obtained from 177 participants (58 autopsy-confirmed AD cases and 119 controls) of the Framingham Heart Study (FHS). 14,15 Sample sizes for analyses of each type of omics data are presented in Tables S2 and S3 in supporting information for the ROSMAP and FHS datasets, respectively. Statistical methods used to analyze these data are presented in the supporting information.…”

Blood and brain transcriptome analysis reveals APOE genotype-mediated and immune-related pathways involved in Alzheimer disease

“…Previous whole transcriptome-wide studies from autopsied brains demonstrate that the classical complement cascade and tau phosphorylation are linked to AD in an APOE genotype-specific manner [14,15]. However, expression profiles associated with AD have not been intensively investigated in the blood and brain from the same individuals, especially separated by the APOE genotype.…”