Apolipoprotein E Isoform-specific changes related to stress and trauma exposure

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Post-Traumatic Stress Disorder (PTSD) prevalence is high, yet therapies remain insufficient due to variable susceptibility and severity.
• Genetic factors, including apolipoprotein E (apoE) isoforms, significantly influence PTSD risk alongside environmental exposures.

Purpose of the Study:

• To investigate the role of apolipoprotein E (apoE) isoforms (E2, E3, E4) in stress-induced behavioral and cognitive changes.
• To explore the association between the apoE E2 genotype and PTSD diagnosis in a human population.

Main Methods:

• Female and male mice expressing human apoE E2, E3, or E4 were exposed to chronic variable stress (CVS) or control conditions.
• Behavioral tests (spatial learning/memory), adrenal gland weight, and biomarker analysis (glucocorticoid receptor, 7-ketocholesterol) were performed.
• Human genotyping of 102 Cambodian and Vietnamese patients was conducted to assess PTSD diagnosis and apoE genotype correlation.

Main Results:

• ApoE E2 mice exhibited unique CVS responses: impaired spatial memory, increased adrenal weight, and unaltered glucocorticoid receptor levels.
• The cholesterol metabolite 7-ketocholesterol increased in E3 and E4 mice but not E2 mice after CVS.
• E2 carriers showed a higher odds ratio for PTSD diagnosis compared to E3/E3 carriers in the human cohort.

Conclusions:

• The apoE E2 isoform confers distinct behavioral, cognitive, and biomarker profiles following stress exposure.
• 7-ketocholesterol may serve as a novel biomarker for the traumatic stress response.
• The apoE E2 genotype is associated with an increased likelihood of PTSD diagnosis after trauma exposure.