Alzheimer?s disease (AD) is a progressive, age-related neurodegenerative disorder and is the most common cause of dementia in elderly individuals. To date, no disease-modifying therapies have been approved for AD, highlighting the need to develop effective treatments. The failures in the creation of disease-modifying therapies is due, in part, to potential deficiencies in our understanding of AD pathogenesis. In addition to plaques composed of ?-amyloid (A?) and neurofibrillary tangles (NFTs) comprised of tau, neuroinflammation is a pathological hallmark of AD. Recently, genome wide association studies (GWAS) have identified genes that modulate risk for the development of AD. Of these identified genes, several are primarily expressed by or highly upregulated in myeloid cells, emphasizing the potential of these cells as contributors to the development of AD. Within the CNS, microglia are the primary resident myeloid cell. We previously determined that administration of colony- stimulating factor 1 receptor (CSF1R) inhibitors eliminate virtually all microglia from the adult mouse brain. We achieve microglia elimination in healthy and disease conditions, allowing us to investigate the roles of these cells in various contexts. To identify the role(s) of microglia in the development of AD, we eliminated 95-100% of microglia brain wide via administration of a CSF1R inhibitor prior to and during the development of plaque pathology in the 5xfAD mouse model of AD. With this treatment paradigm, we find that microglia are necessary for plaque formation. In regions of the brain that exhibited few plaques, these plaques were associated with a small number of surviving microglia, suggesting an involvement of microglia in plaque propagation. Here, I seek to extend upon these findings by 1) assessing the role of microglia in A? seeding in a model of sporadic AD via infusion of A? homogenates from AD patients and 2) identifying the contribution of microglia in plaque expansion by infusing fluorescently labeled A? into 5xfAD animals during the period of plaque development. Collectively, data generated from these aims may strengthen our understanding of mechanisms governing AD pathogenesis and potentially lead to the development of new and effective microglia- based therapies for AD.

Public Health Relevance

Alzheimer?s disease is the most common form of dementia affecting elderly individuals. Recent genetic data implicates alterations in microglia biology as a prominent risk factor for the development of Alzheimer?s disease. Thus, it is imperative to understand the functions these cells exert in the AD brain to create effective disease-modifying therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1)
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Opanashuk, Lisa A
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University of California Irvine
Other Basic Sciences
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United States
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