Abstract
The amyloid hypothesis hinges on the predominant clinical role of the amyloid beta (Aβ) peptide in propagating neurofibrillary tangles and eventual cognitive impairment in Alzheimer’s disease (AD). Recent research in the AD field has identified the brain resident macrophages, known as microglia, and their receptors as integral regulators of both the initiation and propagation of inflammation, Aβ accumulation, neuronal-loss, and memory decline in AD. Emerging studies have also begun to reveal critical roles for distinct innate immune pathways in AD pathogenesis, which has led to great interest in harnessing the innate immune response as a therapeutic strategy to treat AD and other neurodegenerative diseases.
In this dissertation, we highlight recent advances in our understanding of innate immunity and inflammation in AD onset and progression. Additionally, we discuss findings outlining the ability of many AD risk factors to influence disease progression via modulation of microglia and immune responses. Microglia remain a highly targetable cell in neurodegenerative diseases including AD and Multiple Sclerosis (MS). These cells harbor machinery capable of addressing and clearing disease pathology; therefore, enhancement of microglial function is a highly sought-after clinical target. The delineation of specific microglial signaling molecules that modulate cellular response to neurodegenerative pathology is critical for novel treatments that avoid off-target effects during disease.
Utilizing the 5xFAD mouse model of AD, we unearth the mechanisms by which previously under described signaling pathways influence microglial response to Aβ pathology. We identify SYK as the master coordinator of microglial activation to pathology seen in AD. In fact, SYK is necessary for microglial clearance of Aβ in 5xFAD mice and damaged myelin pathology in a model of MS. In addition, we find that SYK directs neuroprotective and targetable downstream signaling to promote phagocytosis of Aβ, including a specific arm of the AKT pathway. These findings uncover a novel microglial signaling molecule that drives cellular function during neurodegeneration and may aid in understanding the continued intricacies of microglial responses during disease.
Additional studies outlined in this dissertation delve into the role of CARD9, a molecule found in microglia and related to fungal response. Using the 5xFAD model, we observe that CARD9 protects against pathology accumulation and regulates microglial cell number and morphological activation. In addition, we observe that the activation of CARD9 drives Aβ clearance. Altogether, these data indicate a novel role for CARD9 in regulating microglial response and ultimately pathology progression in AD.
In summary, this dissertation emphasizes the critical nature of microglial signaling downstream of several receptors implicated in AD. Our work contributes to a more complete understanding of microglial function and upon further investigation may inform consequential therapeutic targets for neurodegenerative disease.
