Abstract
Work from the Lukens lab has shed light on the role of ITAM- and ITIM-associated molecules in the microglial response to Alzheimer’s disease (AD)–related amyloidosis. We showed that loss of the kinase SYK, which functionally abrogates ITAM signaling, impairs microglial phagocytosis and recruitment to amyloid plaques and leads to exacerbated Aβ plaque burden and cognitive deficits. Because SYK initiates a multi-pronged signaling cascade, subsequent work from the Lukens lab focused on identifying downstream pathways that mediate SYK-dependent microglial responses. We found that a SYK–CARD9 signaling axis strongly impacts microglial responses to Aβ pathology. Together, these findings provide mechanistic insight into how microglia are activated and respond during AD-related amyloidosis.
Further work investigated how loss of inhibitory signaling might potentiate the microglial response to amyloid plaque. We found that loss of the inhibitory phosphatase SHIP-1, which is recruited downstream of ITIM signaling and can reverse SYK-mediated activation, led to a hypertrophic microglial response that formed barrier structures more efficiently around plaques and limited local tissue damage. This growing body of work contributes to an improved understanding of how activating and inhibitory signals are balanced by microglia during neurodegenerative disease. To synthesize these findings, Chapter 1 of this thesis presents a literature review focused on ITAM- and ITIM-mediated signaling pathways in microglia.
In Chapter 2 of this thesis, I build upon our understanding of ITAM-associated receptors in AD-related amyloidosis by investigating the role of the microglial receptor CLEC7A in the 5xFAD mouse model. Our motivation to study CLEC7A was twofold. First, increased expression of microglial Clec7a has been observed across multiple models of neurodegeneration and marks a transcriptional shift in a subset of microglia termed disease-associated microglia (DAM). Second, CLEC7A is an ITAM-associated receptor that signals through SYK, leading us to hypothesize that it plays a protective role in disease, consistent with previous findings for other ITAM-associated signaling molecules. We found that loss of Clec7a in CNS-resident macrophages increased Aβ plaque burden and exacerbated neuronal damage. These findings suggest that Clec7a upregulation in microglia responding to neurodegenerative disease is adaptive and aligns with observations made for other ITAM-associated signaling pathways.
In the final chapter of this thesis, I describe the early stages of an investigation into the role of SYK in white matter aging. Although our lab previously demonstrated a role for SYK in the microglial response to Aβ plaques, it remained unclear whether SYK also mediates microglial responses to other aging-related processes that accompany neurodegenerative disease. Prior studies have shown that the ITAM-associated receptor TREM2 protects against white matter degeneration in aged mice, and a growing body of literature supports roles for microglia in maintaining white matter integrity through debris clearance and secretion of trophic factors. Here, I show that SYK partially mediates age-related microglial activation and protects against white matter degeneration. Ongoing and future work will further define how loss of SYK alters the transcriptional profile of aging microglia and affects other CNS cell types within aging white matter.
The appendices of this thesis include a short, invited review describing the diverse mechanisms of neuronal cell death in AD. In recent years, the field has expanded our understanding of the modes of cell death beyond apoptosis and necrosis to include necroptosis, parthanatos, ferroptosis, cuproptosis, and other regulated cell death pathways. This review addresses a gap in the literature by summarizing current understanding of neuronal loss in AD.
