Grant: Operating Grant - Priority Announcement: Aging (Bridge Funding)

Clinical studies reveal that infection-induced systemic inflammation is a risk factor for the future development of Alzheimer's disease. Experiments show that systemic inflammation, via several pathways, can send signals to the brain and activate the central immune system, hence exacerbating aging-related neurodegeneration. However, the mechanism by which systemic inflammation induces central neurodegeneration is largely unclear. In response to inflammatory signals, the prototypic long pentraxin-3 (PTX3) is expressed in various tissues including the brain. PTX3 binds to the complement fragment C1q, activating complement cascades and triggering protease-mediated cell lysis of pathogens and injured cells. Interestingly, a recent study demonstrates that activated complement-cascades, possibly by proteolysis, eliminates unwanted synapses during brain development, but promotes synapse loss in early stages of neurodegeneration. In addition, pentraxins may affect the activity of glycogen synthase kinase (GSK3) a metabolic regulator critically associated with synaptic plasticity and neurodegeneration. This study intends to investigate the cellular and molecular mechanisms by which systemic inflammation induces neurodegeneration using mouse models of lung infection. Specifically, we will examine the role of PTX3 in inflammation-induced synaptic injury in young adult and old mice.