Project Summary/Abstract A large number of studies have provided strong evidence that either periodontitis or metabolic syndrome (MetS) increases risk of Alzheimer’s disease (AD). Given that periodontitis, MetS and AD are all age-related diseases and the prevalence of periodontitis, MetS and AD increases with age, it is likely that periodontitis and MetS coexist in the elderly AD patients. Therefore, it is important to investigate the role of interactive periodontitis and MetS in the pathogenesis of AD. However, no study has been conducted to appraise the impact of the coexistence of periodontitis and MetS on AD. It is known that MetS aggravates periodontitis by increasing systemic and periodontal inflammation. Our lab is the first one to demonstrate that MetS exacerbates periodontitis by increasing systemic and periodontal inflammation in animal models. Thus, we postulated that the interaction between periodontitis and MetS may also aggravate AD by increasing inflammation in the brain. Furthermore, our previous studies showed that acid sphingomyelinase (ASMase)-dependent ceramide production plays an important role in the synergistic stimulation of proinflammatory cytokine expression in macrophages by periodontitis-related lipopolysaccharide (LPS) and MetS-related saturated fatty acid (SFA). Based on these findings, we postulated that ASMase-dependent ceramide production also plays an important role in the exacerbation of AD by comorbidity of periodontitis and MetS. In this study, we proposed two specific aims: 1. To determine the role of the interaction between P. gingivalis-induced periodontitis and high-fat diet (HFD)-induced MetS in the AD progression in mouse models. We hypothesized that P. gingivalis-induced periodontitis and HFD-induced MetS cooperatively exacerbate AD in animal models via ASMase-ceramide pathway-related inflammation. 2. To determine the effect of the interaction between P. gingivalis LPS and SFA on inflammatory response of microglia in vitro and the role of ASMase-ceramide pathway in this interaction. We hypothesized that P. gingivalis LPS and SFAs exert a synergistic upregulation of proinflammatory cytokines in microglia and that ASMase-mediated sphingolipid metabolism plays a key role in the synergism. In this research project, we will conduct both animal studies using AD models and in vitro studies using microglial cells to test our hypothesis. We will employ biochemistry, immunology, cellular and molecular biology techniques to elucidate the underlying mechanisms. We believe that this collaborative study supported by Alzheimer’s-focused administrative supplement will yield novel insights into the pathogenesis of AD. More importantly, this study will facilitate the multidisciplinary collaboration between Dr. Huang and Dr. Bhat and help developing a collaborative research program on AD at MUSC.