Gamma Secretase Activating Protein Promotes End-Organ Dysfunction After Bacterial Pneumonia

Authors

Meredith S. Gwin, University of South Alabama
Mikhail F. Alexeyev, University of South AlabamaFollow
Aron M. Geurts, Medical College of Wisconsin
Ji Young Lee, University of South AlabamaFollow
Chun Zhou, University of South AlabamaFollow
Xi-Ming Yang, University of South AlabamaFollow
Michael V. Cohen, University of South AlabamaFollow
James M. Downey, University of South AlabamaFollow
Robert A. Barrington, University of South AlabamaFollow
Domenico Spadafora, University of South AlabamaFollow
Jonathon P. Audia, University of South AlabamaFollow
Dara W. Frank, Medical College of Wisconsin
Sarah Voth, Edward Via Virginia College of Osteopathic Medicine
Viktoriya V. Pastukh, University of South Alabama
Jessica Bell, University of South Alabama
Linn Ayers, University of South AlabamaFollow
Dhananjay T. Tambe, University of South AlabamaFollow
Amy R. Nelson, University of South AlabamaFollow
Ron Balczon, University of South AlabamaFollow
Mike T. Lin, University of South AlabamaFollow
Troy Stevens, University of South AlabamaFollow

Document Type

Article

Publication Title

American Journal of Physiology-Lung Cellular and Molecular Physiology

Abstract

Pneumonia elicits the production of cytotoxic beta amyloid (Aβ) that contributes to end-organ dysfunction, yet the mechanism(s) linking infection to activation of the amyloidogenic pathway that produces cytotoxic Aβ is unknown. Here, we tested the hypothesis that gamma-secretase activating protein (GSAP), which contributes to the amyloidogenic pathway in the brain, promotes 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 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 wild-type rats, whereas the late long-term potentiation was partially preserved in Gsap knockout rats. Furthermore, hippocampi from knockout rats, and both the wild-type and knockout rats following infection, 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.

NEW & NOTEWORTHY Pneumonia is a common cause of end-organ dysfunction, both during and in the aftermath of infection. In particular, pneumonia is a common cause of lung injury, increased risk of myocardial infarction, and neurocognitive dysfunction, although the mechanisms responsible for such increased risk are unknown. Here, we reveal that gamma-secretase activating protein, which contributes to the amyloidogenic pathway, is important for end-organ dysfunction following infection.

First Page

L174

Last Page

L189

DOI

10.1152/ajplung.00018.2023

Publication Date

8-2023

Department

College of Medicine

Comments

Copyright: © 2023 The Authors. All Rights Reserved.

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Gwin, Meredith S., Mikhail F. Alexeyev, Aron M. Geurts, Ji Young Lee, Chun Zhou, Xi-Ming Yang, Michael V. Cohen et al. "Gamma secretase activating protein promotes end-organ dysfunction after bacterial pneumonia." American Journal of Physiology-Lung Cellular and Molecular Physiology 325, no. 2 (2023): L174-L189.