Impact of Gamma Secretase Activating Protein on End-Organ Dysfunction in the Aftermath of Pneumonia in a Novel Gamma Secretase Activating Protein Knockout Rat
Date of Award
Basic Medical Sciences
Dr. Troy Stevens, Ph.D.
Pneumonia elicits the production of cytotoxic beta amyloid (Aβ) that contributes to endorgan dysfunction, yet the mechanism linking infection to production of cytotoxic Aβ is unknown. Here, we tested the hypothesis that γ-secretase activating protein (GSAP), which promotes Aβ production, contributes to end-organ dysfunction following bacterial pneumonia. First-in-kind GSAP knockout rats were generated. Wild type and knockout rats possessed similar body weights, organ weights, circulating blood cell counts, arterial blood gases, and cardiac indices at baseline. Intratracheal Pseudomonas aeruginosa infection caused acute lung injury and a hyperdynamic circulatory state. Whereas infection led to arterial hypoxemia in wild type rats, the alveolar-capillary barrier integrity was preserved in GSAP knockout rats. Infection provoked neutrophil recruitment to the airways, yet neutrophils in the knockout rats appeared immature. Infection potentiated myocardial infarction following ischemia-reperfusion injury, and this potentiation was abolished in knockout rats. In the hippocampus, GSAP contributed to both pre- and postsynaptic neurotransmission, increasing the presynaptic action potential recruitment, decreasing neurotransmitter release probability, decreasing the postsynaptic response, and preventing postsynaptic hyperexcitability, resulting in greater early long-term potentiation but reduced late long-term potentiation. Infection abolished early and late long-term potentiation in control rats, whereas the late long-term potentiation was preserved in GSAP knockout rats. Furthermore, hippocampi from the knockout rats exhibited a GSAP-dependent increase in neurotransmitter release probability and postsynaptic hyperexcitability. These results elucidate an unappreciated role for GSAP in innate immunity and highlight the contribution of GSAP to end-organ dysfunction during infection.
Gwin, Meredith S., "Impact of Gamma Secretase Activating Protein on End-Organ Dysfunction in the Aftermath of Pneumonia in a Novel Gamma Secretase Activating Protein Knockout Rat" (2023). Theses and Dissertations. 145.