Elucidating the role of CHI3L1/YKL-40 in Alzheimer's disease

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PROJECT SUMMARY/ABSTRACT Chitinase-3-like protein 1 (CHI3L1/YKL-40) is well known as a powerful biomarker for early detection of neuroinflammation and Alzheimer’s disease (AD). While in peripheral tissues CHI3L1 has been well characterized to regulate a wide range of immune and inflammatory responses, how it acts in the brain in the process of neuroinflammation and AD development remains largely unknown. Recent evidence shows that CHI3L1 is primarily secreted by activated astrocytes to signal a neurotoxic inflammatory response across major brain cell types. The dynamic interactions between microglia, astrocytes and neurons are among the major drivers for the inflammatory neurotoxicity underlying development of AD pathology. Disentangling such intricate cellular cross-talk in human neural systems, and the role of CHI3L1 in this process, thus signifies a critical need for developing therapeutics for AD and relevant neurodegenerative disorders. The long-term goal of my laboratory is to understand the pathogenic determinants of neurodegeneration to inform treatments for AD. Using human stem cell-based methodologies, the overall objectives in this application are: i) to define the signaling mechanism whereby CHI3L1 governs glial activation and neurodegeneration; and ii) to develop the translational potential of these signaling mechanisms to prevent neuronal damage in AD. Supported by our preliminary data, our central hypothesis is that astrocyte-derived CHI3L1 functions as a signaling molecule to mediate inflammatory responses in a cell type-specific manner – promoting neuronal degeneration and regulating microglial inflammatory profiles. We also hypothesize that silencing neuronal CHI3L1 signaling will dampen neurotoxicity and ameliorate AD pathogenesis. We propose to exploit iPSC-based pure and mixed human neural cultures (microglia, astrocytes and neurons) to anatomize the inter-cellular interactions and rigorously test our hypotheses. Three specific aims will be pursued to attain the overall objectives: in Aim 1, we will identify the neuronal CHI3L1 receptor and downstream signaling pathway that convey the detrimental effects of CHI3L1 on neurodegeneration in AD, using human neuronal cultures derived from isogenic control and multiple AD mutant iPSC lines (from NIH-funded iNDI); in Aim 2, we will define the CHI3L1-modulated inflammatory properties of microglia in AD, by control and AD mutant iPSC-derived human microglia; in Aim 3, we will decide the mechanism of CHI3L1 function in astrocyte-microglial interactions for neurodegeneration in AD, aided by a reductionist method to dissect the neuroprotective element out of the neuron-glial and glia-glial interactions of neuroinflammation - the tricultures of human microglia, astrocytes and neurons generated from control and AD mutant iPSCs. Our expected outcomes are to define an essential CHI3L1 signaling mechanism governing neuroinflammation underlying AD neurodegeneration. This work will elucidate the biology of a prominent AD biomarker, which will define a new path for AD/ADRD treatment and thus constitutes a significant positive impact.