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Microglial Contributions to Alzheimer’s Disease Pathogenesis


Microglia are the primary central nervous system (CNS) immune cell and carry out a variety of important functions in the brain, including immune defense, regulation of synaptic formation and maintenance, promotion of proper brain connectivity, calcium homeostasis, and trophic support for neurons. Increasing evidence points to a loss of microglial homeostatic functioning in disease conditions, including Alzheimer’s disease (AD), leading to the hypothesis that a failure in immune-related mechanisms contributes to disease progression. Additionally, genome-wide association studies (GWAS) identify variants in myeloid-associated genes as a substantial contributor to AD risk, highlighting the significance of myeloid biology in the development of AD. Thus, intense focus has recently been placed on microglia to identify their roles in AD onset and progression. Importantly, the development of compounds and genetic models to ablate the microglial compartment have emerged as effective tools to further our understanding of microglial function in AD. Previously, we reported that administration of colony-stimulating factor 1 receptor (CSF1R) inhibitors eliminate >99% of microglia brain-wide in the healthy adult murine brain. As an extension of these findings, the goal of my dissertation is to utilize CSF1R inhibitors in mouse models of Alzheimer’s disease to ascertain the various function(s) of microglia in AD pathogenesis. As demonstrated in the first chapter of my dissertation, I administered CSF1R inhibitors to mice to ablate the microglial compartment for one month during advanced stages of pathology in 5xfAD mice, of which 12% of plaque-distal microglia survived CSF1R inhibitor treatment whereas 50% of plaque-associated microglia remained. With this paradigm, I observed improvements in contextual fear memory, normalized brain-wide inflammatory signaling, the regeneration of lost dendritic spine densities, and additionally, the absence of microglia prevented neuronal loss. These data indicate that, during the later stages of disease, primarily plaque-distal microglia mount a detrimental and non-resolving inflammatory response in the AD brain that damages synapses and neurons, ultimately impairing cognitive function, whereas plaque-associated microglia exert neuroprotective effects. Importantly, microglial ablation in advanced pathology AD mice did not modulate β-amyloid (Aβ) burden in the brain, possibly due to a loss of microglial Aβ clearance capabilities during advanced stages of AD. As previously stated, myeloid biology is heavily implicated in the development of AD, via GWAS; thus, I next sought to explore the contributions of microglia in disease onset. To that end, I eliminated microglia prior to the onset of pathology, as well as throughout the course of disease in chapter two. As microglia are phagocytic cells, if the degradation of Aβ by microglia in early AD protects against Aβ accumulation and deposition, perturbing this process while microglia are functional phagocytes should dramatically elevate Aβ pathology. Contrary to expectations, I found that lifelong ablation of microglia prevented parenchymal plaque burden, except in areas where microglia survived CSF1R inhibition, indicating that microglia are facilitate plaque formation. In chapter three of the dissertation, I expanded upon these findings and identify microglial Apolipoprotein E (ApoE) as a contributor to plaque formation in 5xfAD mice. Collectively, these results highlight a spectrum of microglial functional states, dependent on disease stage (i.e., Aβ pathology onset and disease severity) and proximity to Aβ plaques, and demonstrate that microglia act as critical and causative agents in the onset and development of AD pathology.

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