Unrestrained inflammation of the central nervous system (CNS) precipitates and exacerbates a wide range of debilitating neurodegenerative diseases, including Alzheimer?s disease (AD), yet our understanding of the mechanisms that regulate neuroinflammation is incomplete. Microglia, the distinctive tissue macrophages of the CNS, display two coupled activities that are fundamental to this regulation ? the inhibition of neurotoxic inflammatory cytokines and chemokines, and the phagocytosis of apoptotic cells and membranes. Multiple lines of evidence demonstrate that these coupled microglial activities are controlled by signaling through TAM receptor tyrosine kinases. The experiments of this proposal address how the TAM receptors Axl and Mer (gene name Mertk), whose microglial expression is markedly elevated in AD and its animal models, act to restrain disease.
In Aim 1, genetic and cell biological methods that exploit mouse models of AD will be used to quantify expression of TAM signaling components in the CNS with respect to amyloid burden, cytokine expression, and lifespan during the course of disease.
In Aim 2, mice that carry Axl and Mertk mutations, or mutations in the genes encoding the TAM ligands Gas6 and Pros1, will be crossed to AD models to assess how global loss of TAM signaling affects the course of disease. Survival, cytokine elevation, amyloid burden, physiological dysfunction, and cognitive decline will be quantified in these compound mutants. Tests will also be performed to quantify the effects of drugs that inhibit TAM receptor activity, or alternatively, boost TAM receptor expression, on AD development and progression. Several TAM inhibitors are now being given to patients in clinical trials as cancer therapies, with no appreciation of their potential effect on AD.
In Aim 3, cell-specific inactivation of the Axl and Mertk genes - only in microglia, or alternatively, only in TAM-expressing brain vascular endothelial cells - will be performed. Analyses of these mice will quantify the relative contribution of TAM action in each of these cell types to the control of AD. Together, these studies will delineate the molecular, cellular, and physiological features of a fundamental pathway of immune homeostasis in the CNS, and elucidate how TAM receptors and their ligands may be exploited as new targets for therapeutic intervention in AD and other neurodegenerative disorders.

Public Health Relevance

More than five million Americans are currently living with Alzheimer?s Disease (AD), and there are no therapies that slow, halt, or reverse its progression. Axl and Mer - the receptor tyrosine kinases addressed by this proposal ? are hypothesized to act in the brain to restrain AD and other neurodegenerative diseases. As these receptors are already drug targets, a mechanistic understanding of their role in neurodegeneration is of immediate importance to public health.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Cell Death in Neurodegeneration Study Section (CDIN)
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Opanashuk, Lisa A
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Salk Institute for Biological Studies
La Jolla
United States
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