ABCA1 haplodeficiency affects the brain transcriptome following traumatic brain injury in mice expressing human APOE isoforms.
Emilie L CastranioCody M WolfeKyong Nyon NamFlorent LetronneNicholas F FitzIliya LefterovRadosveta KoldamovaPublished in: Acta neuropathologica communications (2018)
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.
Keyphrases
- traumatic brain injury
- cognitive decline
- genome wide
- high fat diet
- high fat diet induced
- inflammatory response
- brain injury
- immune response
- poor prognosis
- mild cognitive impairment
- network analysis
- copy number
- dna methylation
- severe traumatic brain injury
- binding protein
- gene expression
- single cell
- wild type
- neuropathic pain
- type diabetes
- metabolic syndrome
- nitric oxide
- small molecule
- dendritic cells
- genome wide analysis
- multiple sclerosis
- fatty acid
- functional connectivity
- cerebral ischemia
- skeletal muscle
- transcription factor
- lps induced
- resting state
- protein protein
- white matter
- smoking cessation
- pluripotent stem cells