The Neuronal Effect of CHI3L1 in Neuroinflammation & Alzheimer's Disease - PROJECT SUMMARY One in three Americans will be diagnosed with Alzheimer’s disease (AD) if no new prevention and intervention strategies are developed. The pathological hallmarks of AD include accumulation extracellular amyloid plaques consisting of amyloid beta (Aβ), processed from amyloid precursor protein (APP), and intracellular neurofibrillary tangles comprised of phospho-tau. These features are proceeded and precipitated by a wide range of intra- and inter-cellular functions, with derailed neuroinflammation being among the earliest manifestations in human brains. Of note, Chitinase-3-like protein 1 (CHI3L1, or YKL-40), an inflammatory protein mainly secreted by reactive astrocytes in the brain, has been documented to be a powerful AD biomarker, and its cerebrospinal fluid (CSF) level has recently been reported to be potentially the first disease indicator. However, how it functions in the brain and influences neuroinflammation and AD pathogenesis remains to be elucidated. In contrast, in peripheral tissues such as in the pulmonary system, CHI3L1 has been well characterized as an immune signaling molecule that controls many aspects of inflammatory processes via specific cell surface receptors and downstream signaling pathways. Teaming up with leading expertise in CHI3L1 biology in lung diseases, the Huang laboratory has gathered evidence showing that CHI3L1 is expressed more abundantly in astrocytes from AD brains and can mediate the inflammatory signaling and cellular responses as in the periphery. Supported by my own preliminary data, my central hypothesis is that CHI3L1 secreted by activated astrocytes engages a neuronal receptor and triggers a signaling cascade in neurons that contributes to the inflammatory neurotoxicity and leads to neurodegeneration and relevant AD features. My overall objective here is to define a neuronal signaling mechanism whereby CHI3L1 regulates glia-derived neuroinflammatory response and the resultant neurodegeneration. By using human neurons generated from pluripotent stem cells in single cultures and a Chi3l1-floxed mouse strain, I propose to pursue two specific aims in order to test my hypothesis and achieve the objective. In Aim 1, I will identify the CHI3L1 receptor and downstream signaling pathway in stem cell-derived human neurons in vitro. In Aim 2, I will determine the effects of CHI3L1 expression on inflammatory neurotoxicity in vivo in transgenic mouse brains with conditional Chi3l1 knockout and expression of AD pathology. My expected outcome is to elucidate an essential signaling function of CHI3L1 in neurons in response to neuroinflammatory stress. My results will reveal a mechanistic role CHI3L1 plays in the brain, departing from being merely a biomarker for AD and neuroinflammation. There will be a positive impact as my findings can be used in targeted therapeutics to combat AD. Finally, the primary responsibility of a F31 awardee is, in lieu of performing experiments, to prepare him/herself for future success in research. With this regard, my major goal of award period is to leverage the rich resources at Brown and execute a rigorous training plan that will impart to me the skills, ingenuity and experimental acumen necessary for growth into an independent investigator.
