Alzheimer’s disease (AD) is the leading cause of dementia and is characterized by accumulation of amyloid species into extracellular plaques as well as hyperphos- phorylated intracellular tau tangles. Microglia, the immune cells of the brain, play a critical role in amyloid clearance via phagocytosis and contribute to inflamma- tory cytokine production in AD. Thus, understanding the molecular mechanisms that facilitate microglial phagocytosis and suppression of inflammation will be critical to developing highly targeted therapies. Our lab and others have observed a robust increase in Axl receptor expression on microglia directly surrounding amyloid plaque. Axl, a receptor tyrosine kinase, is an intriguing target to study in the context of AD because its downstream signaling includes both initiation of phagocytosis and activation of transcription factors that suppress proinflammatory cytokine production. However, there is a distinct paucity of literature examining the role of Axl in microglia and in the context of AD. This work utilizes in vitro and in vivo systems to investigate whether and how activation of Axl by its natural ligand Gas6 promotes amyloid plaque clearance and modulates inflammation in mouse models of acute neuroinflammation and AD.
To address these hypotheses, adeno-associated viruses harboring the Gas6 se- quence or an attenuated, nonfunctional Gas6 sequence as a control were developed and injected into hippocampi of APP/PS1 mice, which develop amyloid plaques by ten months of age, and 3xTg mice, which develop hyperphosphorylated tau tangles and amyloid beta plaques by eighteen months of age. This work demonstrates that chronic overexpression of Gas6 reduces amyloid beta plaque burden in male APP/PS1 mice and increases phosphorylation of pathologic tau in male 3xTg mice. Behavioral assays sought to determine whether the reduction in plaque is accompanied by improvement in hippocampal-dependent tasks, and immunohisto- chemical and molecular analyses assessed changes in phagocytic and inflammatory markers following overexpression of Gas6. In vitro phagocytosis assays were used to address whether Gas6 improves the ability of microglia to phagocytose amyloid beta. Finally, we evaluated the role of Gas6 as an anti-inflammatory mediator in the CNS using an acute model of lipopolysaccharide injection. Together, these results contribute to an understanding of the Gas6-Axl interaction in inflammatory and neurodegenerative settings.
|Advisor:||O'Banion, M. Kerry|
|Commitee:||Olschowka, John, Johnson, Gail, Elliott, Michael, Kiernan, Amy|
|School:||University of Rochester|
|Department:||School of Medicine and Dentistry|
|School Location:||United States -- New York|
|Source:||DAI-B 82/7(E), Dissertation Abstracts International|
|Keywords:||Alzheimer's disease, Axl, Microglia, Neuroinflammation, TAM receptors|
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