Chronic neuroinflammation of the olfactory epithelium, as occurs in chronic rhinosinusitis (CRS), results in the loss of the sense of smell, due in part to cytokine-mediated neuronal death and inhibition of olfactory regeneration. Within the scope of the parent grant, the exploration of the effect of chronic neuroinflammation on the olfactory system extends to the axonal projections of the olfactory epithelium to the olfactory bulb (OB). In the brain, including the OB, neuro-immune interactions are increasingly believed to play an important role in the pathogenesis of Alzheimer's disease (AD) and its related dementias. Neuroinflammation is a prominent feature of AD that is highly correlated with disease escalation. The precise etiologic relationship between inflammation and AD histopathology is uncertain, but recent evidence increasingly suggests that systemic inflammatory disease is a risk factor and exacerbator of ADRD. The OB, which is an early site of AD histopathologic change, is connected and in close proximity to the olfactory epithelium. Directly exposed to the outside environment, the delicate olfactory neuroepithelium is subject to microbial exposures and local immune responses. In chronic rhinosinusitis, the olfactory epithelium becomes infiltrated with inflammatory cells producing a variety of pro-inflammatory mediators. A case-control study has linked dementia with a history of chronic rhinosinusitis, suggesting that longstanding nasal inflammation may propagate effects to the brain. The major goal of this project is to use a mouse genetic model of chronic olfactory epithelial inflammation to investigate whether neuroinflammation spreads to the OB over time, either driving deposition of amyloid plaques and neurofibrillary tangles, or exacerbating disease histopathology in mouse AD models. We further plan to investigate the role of the MAP kinase JNK in AD pathophysiology, which is an inflammatory signaling mediator that we have been studying as a therapeutic target for olfactory neuroprotection in CRS. Using genetically-modified mouse strains and pharmacologic agents, we will explore the roles of specific cytokines implicated in ADRD in mediating olfactory inflammation-induced AD-like changes in the OB, and whether these can be modulated by inhibiting JNK activity. The experiments described in this proposal will afford new insights into neuroinflammatory mechanisms that may trigger early stages of ADRD.
The loss of the sense of smell is an early sign of Alzheimer's disease and a common symptom of chronic sinusitis, both associated with inflammation of olfactory neural tissue. In this proposal, we utilize mouse models to study how olfactory inflammation may extend to the brain and contribute to the development or progression of Alzheimer's disease. The experiments will provide new insights into the potential role of chronic nasal inflammation in driving or exacerbating neuroinflammation, which will potentially lead to novel therapeutic approaches.