TY - JOUR
T1 - Apolipoprotein E Isoform-specific changes related to stress and trauma exposure
AU - Torres, Eileen Ruth S.
AU - Luo, Jenny
AU - Boehnlein, James
AU - Towns, Daniel
AU - Kinzie, J. David
AU - De Barber, Andrea
AU - Raber, Jacob
N1 - Funding Information:
The authors wish to thank Andrea Anaya, Skyler Younger, Hayley VanderJagt, Esha Patel, and Sydney Weber Boutros for help with dissections and tissue preparation, Hannah Kapoor for help with data analysis, and Dr. Joachim Herz for generously supplying LDLR antibody. They thank Kim Truong-Pham, Kanya Pou, and Loan Huynh for their services as counselors at the clinic and aiding with translating and collecting the saliva samples. They also thank Dr. Clive Woffendin and his staff at Oregon Clinical and Translational Research Institute for genotyping. Thank you to Reed Hall for his help with sorting the data. They wish to also thank Drs. Steven G. Kohama, Miranda M Lim, Charles E. Roselli, and Deborah A. Finn for providing feedback on the manuscript. Funding: OHSU Dean’s Fund (ERT), T32DA007262-25 (ERT), OHSU Core Pilot Grant (AD, JR), DOD grant W81XWH-17-1-0193 (JR), NIH grant RF1 AG059088 (JR), and JR’s development account.
Funding Information:
The authors wish to thank Andrea Anaya, Skyler Younger, Hayley VanderJagt, Esha Patel, and Sydney Weber Boutros for help with dissections and tissue preparation, Hannah Kapoor for help with data analysis, and Dr. Joachim Herz for generously supplying LDLR antibody. They thank Kim Truong-Pham, Kanya Pou, and Loan Huynh for their services as counselors at the clinic and aiding with translating and collecting the saliva samples. They also thank Dr. Clive Woffendin and his staff at Oregon Clinical and Translational Research Institute for genotyping. Thank you to Reed Hall for his help with sorting the data. They wish to also thank Drs. Steven G. Kohama, Miranda M Lim, Charles E. Roselli, and Deborah A. Finn for providing feedback on the manuscript. Funding: OHSU Dean?s Fund (ERT), T32DA007262-25 (ERT), OHSU Core Pilot Grant (AD, JR), DOD grant W81XWH-17-1-0193 (JR), NIH grant RF1 AG059088 (JR), and JR?s development account.
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - Post-Traumatic Stress Disorder (PTSD) is a highly prevalent mental health disorder. Due to the high level of variability in susceptibility and severity, PTSD therapies are still insufficient. In addition to environmental exposures, genetic risks play a prominent role and one such factor is apolipoprotein E. The protein (apoE) is functionally involved in cholesterol transport and metabolism and exists as 3 major isoforms in humans: E2, E3, and E4. To model the role of apolipoprotein E isoform in stress-related changes in behavior and cognition, female and male mice (3–5 months of age) expressing E2, E3, or E4 were used. Mice were either placed into control groups or exposed to chronic variable stress (CVS), which has been shown to induce PTSD-like behavioral and neuroendocrine changes. E2 mice showed a unique response to CVS compared to E3 and E4 mice that included impaired spatial learning and memory, increased adrenal gland weight, and no increase in glucocorticoid receptor protein levels (normalized to apoE levels). In addition, the cholesterol metabolite 7-ketocholesterol was elevated in the cortex after CVS in E3 and E4, but not E2 female mice. E2 confers unique changes in behavioral, cognitive, and biomarker profiles after stress exposure and identify 7-ketocholesterol as a possible novel biomarker of the traumatic stress response. We further explored the relationship between E2 and PTSD in an understudied population by genotyping 102 patients of Cambodian and Vietnamese ethnicity. E2 carriers demonstrated a higher odds ratio of having a PTSD diagnosis compared to E3/E3 carriers, supporting that the E2 genotype is associated with PTSD diagnosis after trauma exposure in this population.
AB - Post-Traumatic Stress Disorder (PTSD) is a highly prevalent mental health disorder. Due to the high level of variability in susceptibility and severity, PTSD therapies are still insufficient. In addition to environmental exposures, genetic risks play a prominent role and one such factor is apolipoprotein E. The protein (apoE) is functionally involved in cholesterol transport and metabolism and exists as 3 major isoforms in humans: E2, E3, and E4. To model the role of apolipoprotein E isoform in stress-related changes in behavior and cognition, female and male mice (3–5 months of age) expressing E2, E3, or E4 were used. Mice were either placed into control groups or exposed to chronic variable stress (CVS), which has been shown to induce PTSD-like behavioral and neuroendocrine changes. E2 mice showed a unique response to CVS compared to E3 and E4 mice that included impaired spatial learning and memory, increased adrenal gland weight, and no increase in glucocorticoid receptor protein levels (normalized to apoE levels). In addition, the cholesterol metabolite 7-ketocholesterol was elevated in the cortex after CVS in E3 and E4, but not E2 female mice. E2 confers unique changes in behavioral, cognitive, and biomarker profiles after stress exposure and identify 7-ketocholesterol as a possible novel biomarker of the traumatic stress response. We further explored the relationship between E2 and PTSD in an understudied population by genotyping 102 patients of Cambodian and Vietnamese ethnicity. E2 carriers demonstrated a higher odds ratio of having a PTSD diagnosis compared to E3/E3 carriers, supporting that the E2 genotype is associated with PTSD diagnosis after trauma exposure in this population.
UR - http://www.scopus.com/inward/record.url?scp=85127288135&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127288135&partnerID=8YFLogxK
U2 - 10.1038/s41398-022-01848-7
DO - 10.1038/s41398-022-01848-7
M3 - Article
C2 - 35347119
AN - SCOPUS:85127288135
VL - 12
JO - Translational Psychiatry
JF - Translational Psychiatry
SN - 2158-3188
IS - 1
M1 - 125
ER -