| Description: |
Pneumonia elicits the production of cytotoxic beta amyloid (Ab) that contributes to end-organ dysfunction, yet the mechanism(s) link- ing infection to activation of the amyloidogenic pathway that produces cytotoxic Ab 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 dys- function following bacterial pneumonia. First-in-kind Gsap knockout rats were generated. Wild-type and knockout rats possessed simi- lar 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 myocar- dial 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 neu- rotransmitter 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 neurotrans- mitter release probability and postsynaptic hyperexcitability. These results elucidate an unappreciated role for GSAP in innate immu- nity 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 ... |