Peripheral manifestation of brain inflammation: signaling mechanisms

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PROJECT SUMMARY Olfactory sensory neurons (OSNs), residing in olfactory epithelium (OE), send axon directly into olfactory bulb (OB) in the brain. This anatomical feature, unique among all sensory systems, exposes the brain directly to the environment. It is known that early stages of Alzheimer Disease (AD) are reflected in olfactory dysfunction. OB in the brain shows very early neuropathology in AD. It is well-established knowledge that AD progression is correlated with neuroinflammatory events in the brain, however, there is currently no reliable means for early detection of these events. Our preliminary data indicate that OE responds to increased levels of cytokines and pathogenic events in the OB, likely through retrograde signaling via the olfactory nerve. Retrograde signaling to trophic factors along axons from terminal to cell body is well known. We hypothesize that OE is a sensitive site to detect brain inflammation via retrograde inflammatory cytokine signaling through the olfactory nerve. To test this hypothesis, we will systematically characterize transcriptional changes in responding amyloid plaque induced inflammation. Signaling mechanisms will be investigated to gain understanding of critical cellular processes involved. The long-term goal of this study is to gain understanding of the molecular mechanisms of peripheral organ and brain communication of inflammation in neurodegenerative diseases.