A Refined Murine Model of Post-sepsis Cognitive Impairment for Investigating Mitochondrial Abnormalities and Human ApoE4 Gene Polymorphisms

ABSTRACT Sepsis is an infection-initiated life-threatening medical condition accompanied by severe whole-body inflammation. Over 1.7 million sepsis survivors are now discharged from the hospital annually, and a majority of them report reduced quality of life due to considerable long-term dysfunction, called chronic critical illness, including muscle weakness and cognitive impairment after hospital discharge. We previously developed a clinically relevant murine sepsis-survivor model with an ICU-like resuscitation procedure that enables us to evaluate long-term muscle quality and function after recovery from sepsis. Our studies demonstrated that sepsis-survivor mice exhibit significant skeletal muscle weakness. Skeletal muscles from these sepsis-survivor mice also show profound mitochondrial structural and functional defects. In contrast to muscle dysfunction, little is known for cognitive dysfunction in sepsis survivors. Although there are several published studies using laboratory animal models for this issue, their results remain inconclusive due to several limitations; 1) cognitive impairment being assessed by stressful swimming maze tests which sepsis survivors perform poorly due to muscle weakness; 2) use of surgical sepsis models with artifactual necrosis and resulting systemic inflammation; and 3) the lack of antibiotics treatment and the lack of confirmation of sepsis recovery, thereby focusing on dysfunction “during sepsis” rather than “post-sepsis”, all limit current research. Importantly, all these limitations are resolved in our above-mentioned sepsis-survivor mouse model that confirms complete recovery from sepsis, allows sufficient duration (4 weeks or longer) after sepsis to study long term effects, and eliminates surgical procedures to avoid artifactual necrosis and inflammation. Thus, our well-refined sepsis- survivor mouse model for muscle weakness can potentially be an appropriate animal model to investigate post- sepsis long-term cognitive impairment. Our major hypothesis is that this sepsis-survivor model will exhibit long- term cognitive impairment. We also hypothesize that ApoE4 gene polymorphism, the most common AD- susceptible genotype, confers a higher risk of developing cognitive dysfunction after surviving sepsis. Additionally, we hypothesize that mitochondrial abnormalities are involved in such post-sepsis cognitive impairment. To test these hypotheses, two Specific Aims will be pursued. (1) To test whether wild type mice develop long-term cognitive impairment after sepsis; and (2) To test whether mutant mice carrying the human ApoE4 gene polymorphism have a higher risk of developing cognitive impairment after sepsis.