Victor Kruglov

Age is the greatest risk factor for many chronic diseases, including Alzheimer’s Disease (AD), and is characterized by chronic, low-grade inflammation termed “inflammaging”. Macrophages, an innate immune cell, are activated by the age-related accumulation of damage-associated molecular patterns (DAMPs), including amyloid-beta, cholesterol, and necrotic cell debris. This stimulates the NLRP3 inflammasome and caspase-1 leading to increased inflammatory cytokines. Nlrp3-deficient mice have reduced age-related inflammation and inhibiting the inflammasome activation reduces AD-pathology. We have recently shown that increased Gdf3 expression in macrophages from old mice is reduced by Nlrp3-deficiency. Furthermore, Gdf3-/- macrophages have reduced levels of cytokine transcript and caspase-1 activation after inflammasome activation. However, it is unclear how GDF3 regulates the NLRP3 inflammasome activation during aging and AD. I hypothesize that Gdf3 and its receptors (activin receptor type I/II) are increased with the NLRP3 inflammasome activation. I will test this hypothesis by using quantitative PCR to determine the expression levels of Gdf3, and activin receptors in tissue that have been exposed to DAMPs. I found that GDF3 increased significantly in 7 out of 12 separate tissues with age. The receptors were differentially regulated across tissues. In vitro, macrophages had no changes in Gdf3 expression, with decreases in Acvr2b. In the future, macrophages will be stimulated with amyloid-beta to mimic their activation during AD. I will examine SMAD signaling and test for the role of GDF3 using GDF3-deficient mice. These experiments will better elucidate how GDF3 regulates NLRP3 inflammation to promote inflammaging leading to AD.