Protein phosphatase 2A, complement component 4, and <i>APOE</i> genotype linked to Alzheimer’s disease using a systems biology approach
Bibliographic record
Abstract
ABSTRACT Background Recent 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. Methods The 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. Results Of 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 Aβ 42 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 Aβ 42 , 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. Conclusion We demonstrated for the first time a molecular link between a tau phosphatase and the classical complement pathway, especially C4, and AD-related tau pathology.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".