Integrative Brain Transcriptome Analysis Links Complement Component 4 andHSPA2to theAPOEε2 Protective Effect in Alzheimer Disease

Abstract

Mechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer’s disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ε 2/ε 3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ε 2/ε 3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting this APOE ε 2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.

Blood and Brain Transcriptome Analysis Reveals APOE Genotype-mediated and Immune-related Pathways Involved in Alzheimer Disease

“…FASTQ single nuclei RNA-sequencing data from the prefrontal cortex of 48 brains from ROSMAP participants (24 AD cases, 24 controls) were obtained from the Synapse portal [15] and processed as previously described [12]. The average expression for each cell-type in the blood and brain RNA-seq datasets was calculated for each gene.…”

“…Of these 639 samples, data from 576 samples with both RNA integrity number (RIN) and post-mortem interval (PMI) were included in subsequent differential expression analyses (Supplementary Table 1). Previously reported RNA-seq data were also available which were derived from the frontal cortex tissue region of 208 frontal autopsied brains (64 AD and 129 controls) donated to the Framingham Heart Study and Boston University Alzheimer's Disease Center (FHS/ADRC) [12]. A diagnosis of AD in these brains was established using NIA-Regan criteria including Braak staging and CERAD score [12].…”

“…Previously reported RNA-seq data were also available which were derived from the frontal cortex tissue region of 208 frontal autopsied brains (64 AD and 129 controls) donated to the Framingham Heart Study and Boston University Alzheimer's Disease Center (FHS/ADRC) [12]. A diagnosis of AD in these brains was established using NIA-Regan criteria including Braak staging and CERAD score [12].…”

“…We used gene expression levels calculated as log-transformed fragments per kilobase of transcript per million (FPKM). Soft-power parameters of 12.0 and 12.5 were selected for analyses of brain and blood data, respectively, as previously described [12]. Expression data were clustered hierarchically by implementing a dissimilatory topological overlap matrix (TOM).…”

“…Previous whole transcriptome-wide studies from autopsied brains demonstrate that the classical complement cascade and tau phosphorylation are linked to AD in an APOE genotypespecific manner [12,13]. However, expression profiles associated with AD has not been intensively investigated in blood and brain from the same individuals, especially separated by APOE genotype.…”