Cited by 23Traumatic Brain Injury and Neurovascular DisturbancesTraumatic Brain Injury ResearchNeuroinflammation and Neurodegeneration Mechanisms

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

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Castranio, Emilie L., Wolfe, Cody M., Nam, Kyong Nyon, Letronne, Florent, Fitz, Nicholas F., Lefterov, Iliya, Koldamova, Radosveta·2018·Acta Neuropathologica Communications

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.

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  • BNIP3 encodes BCL2 interacting protein 3, which is increased in hypoxic-ischemic-encephalopathy and physiological ageing, and increases in association with cellular senescence especially in cells over-expressing p21 and p16.

    “BNIP3 (FC = 1.17, p = 0.04) encodes BCL2 interacting protein 3, which is increased in hypoxic-ischemic-encephalopathy [18] and physiological ageing [31], and has been shown to increase in association with cellular senescence especially in cells over-expressing p21 and p16 [16].”

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Authors
Castranio, E. L., Wolfe, C. M., Nam, K. N., Letronne, F., Fitz, N. F., Lefterov, I., & Koldamova, R.
Affiliations
University of Pittsburgh (US)
Corresponding author
  • Lefterov, Iliya
  • Koldamova, Radosveta
Venue
Acta Neuropathologica Communications
Published
2018-07-26
Volume
6
Issue
1
Pages
69-69
ISSN
2051-5960 (ISSN-L)
OpenAlex
W2884483584
Cited by
23
References
50
Citations by year
2026: 1 · 2025: 1 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 8
FWCI
2.55
Type
journal article
Language
en
Open access
Locations
  • Acta Neuropathologica Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Defense (W81XWH-13-1-0384)
  • National Institute on Aging (K01AG044490, AG056371, AG057565)
  • National Institute of Environmental Health Sciences (ES024233)
Topics
  • Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
  • Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
traumatic brain injury, apolipoprotein E, APOE ε4, microglia, transcriptome, controlled cortical impact, gene co-expression network, TREM2, TYROBP, CD68, HEXB, inflammation, lipid modification, targeted replacement mice
MeSH terms
Brain Injuries, Traumatic, Animals, Apolipoproteins E, Brain, Disease Models, Animal, Gene Expression Regulation, Humans, Mice, Inbred C57BL, Mice, Transgenic, RNA, Messenger, Microglia, Protein Isoforms, Mice, Gene Regulatory Networks, ATP Binding Cassette Transporter 1

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