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The role of apolipoprotein E in traumatic brain injury as determined by isoform and Abca1 haplodeficiency

Castranio, Emilie L. (2018) The role of apolipoprotein E in traumatic brain injury as determined by isoform and Abca1 haplodeficiency. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Traumatic brain injury (TBI) is a significant public health concern as one of the leading causes of death and disability in the United States. TBI is due to the head forcibly contacting another object, or other mechanisms causing displacement of the brain within the skull. TBI is a complex multimodal disease process associated with high heterogeneity in outcomes, which suggests significant influence by genetic factors. Recent studies implicate the apolipoprotein E (APOE) gene in modulating TBI outcomes in an isoform-specific manner, specifically with inheritance of the APOE4 allele conferring worse outcome. The isoform-specific effect may be modulated by ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein that mediates the transport of lipids and cholesterol onto APOE, impacting its lipidation and stability.
First, we examined whether there is an APOE isoform-specific response to TBI using mice expressing human APOE3+/+ or APOE4+/+ isoforms. At 3-months-old, TBI-treated mice received a craniotomy followed by a controlled cortical impact in the left hemisphere, whereas sham-treated mice received only a craniotomy. We found that both isoforms demonstrated similar cognitive impairments and transcriptional profiles following moderate TBI. We then examined the impact of ABCA1 deficiency on the response to traumatic brain injury using human APOE3+/+ and APOE4+/+ targeted replacement mice with only one functional copy of the Abca1 gene (E3/Abca1+/-; E4/Abca1+/-). We observed a common transcriptional response to TBI among the genotypes – E3/Abca1+/+, E4/Abca1+/+, E3/Abca1+/-, E4/Abca1+/- – however, E4/Abca1+/- had the highest proportion of unique transcripts. Additionally, we found that Abca1 haploinsufficiency increased the expression of microglia sensome genes among only APOE4 injured mice. Our results suggest that the APOE4 isoform is more susceptible to the consequences of Abca1 haplodeficiency.
To identify modules, or interconnected gene clusters, correlated to TBI, APOE isoform, and Abca1 haplodeficiency, we performed Weighted Gene Co-expression Network Analysis (WGCNA). We determined that the module most correlated to TBI, regardless of APOE isoform or Abca1 deficiency, represented “immune response” with major hub genes including microglia-specific genes Trem2, Tyrobp, and Cd68. Unique modules were also associated with APOE isoform, and Abca1 haplodeficiency. Our results identify genes with a potential to become useful targets for future research.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Castranio, Emilie L.elc72@pitt.eduelc720000-0001-6817-7388
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBarchowsky, Aaronaab20@pitt.eduaab20
Thesis AdvisorLefterov, Iliyailiya.lefterov@pitt.eduiliyal
Committee MemberKoldamova, Radosvetaradak@pitt.eduradak
Committee MemberDixon, C. Edwarddixoec@upmc.eduedixon
Date: 25 September 2018
Date Type: Publication
Defense Date: 12 July 2018
Approval Date: 25 September 2018
Submission Date: 10 July 2018
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 121
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Apolipoprotein E, Traumatic brain injury, Abca1 haplodeficiency, microglia, transcriptome, WGCNA
Date Deposited: 25 Sep 2018 20:28
Last Modified: 25 Sep 2018 20:28
URI: http://d-scholarship.pitt.edu/id/eprint/34615

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