ABCA1 haplodeficiency affects the brain transcriptome following traumatic brain injury in mice expressing human APOE isoforms

Abstract

Expression of human Apolipoprotein E (APOE) modulates the inflammatory response in an isoform specific manner, with APOE4 isoform eliciting a stronger pro-inflammatory response, suggesting a possible mechanism for worse outcome following traumatic brain injury (TBI). APOE lipidation and stability is modulated by ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein that transports lipids and cholesterol onto APOE. We examined the impact of Abca1 deficiency and APOE isoform expression on the response to TBI using 3-months-old, human APOE3+/+ (E3/Abca1+/+) and APOE4+/+ (E4/Abca1+/+) targeted replacement mice, and APOE3+/+ and APOE4+/+ mice with only one functional copy of the Abca1 gene (E3/Abca1+/−; E4/Abca1+/−). TBI-treated mice received a craniotomy followed by a controlled cortical impact (CCI) brain injury in the left hemisphere; sham-treated mice received the same surgical procedure without the impact. We performed RNA-seq using samples from cortices and hippocampi followed by genome-wide differential gene expression analysis. We found that TBI significantly impacted unique transcripts within each group, however, the proportion of unique transcripts was highest in E4/Abca1+/− mice. Additionally, we found that Abca1 haplodeficiency increased the expression of microglia sensome genes among only APOE4 injured mice, a response not seen in injured APOE3 mice, nor in either group of sham-treated mice. To identify gene networks, or modules, correlated to TBI, APOE isoform and Abca1 haplodeficiency, we used weighted gene co-expression network analysis (WGCNA). The module that positively correlated to TBI groups was associated with immune response and featured hub genes that were microglia-specific, including Trem2, Tyrobp, Cd68 and Hexb. The modules positively correlated with APOE4 isoform and negatively to Abca1 haplodeficient mice represented “protein translation” and “oxidation-reduction process”, respectively. Our results reveal E4/Abca1+/− TBI mice have a distinct response to injury, and unique gene networks are associated with APOE isoform, Abca1 insufficiency and injury.

The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

“…The density and size of these particles are similar to those of plasma HDL [148]. ABCA1 contributes to cholesterol homeostasis and participates in the pathophysiology of neurological diseases involving the accumulation of proteins in brain cells, such as traumatic brain injury, stroke sequelae, Parkinson's disease, and Alzheimer's disease (AD) [149][150][151][152][153][154][155][156][157].…”

Gene Expression Signature of Traumatic Brain Injury

“…By coexpression analysis for DEGs, we identified gene sets (modules) with coexpression patterns. Each module may characterize different molecular mechanisms of action (Castranio et al, 2018 ). Among them, the crosstalk between modules 1, 4, and 7 was the most obvious.…”

Identification of target genes in neuroinflammation and neurodegeneration after traumatic brain injury in rats

“…Axonal repair is important for the recovery of brain injury. ABCA1 is a major regulator of cellular cholesterol and phospholipid homeostasis necessary for axonal restoration, which transports lipids and cholesterol onto APOE (Castranio et al, 2018). Meanwhile, MAG, which is a transmembrane glycoprotein localized in periaxonal cells, plays a role in the inhibition of nerve regeneration after injury in the CNS (Yiu & He, 2006).…”