Mechanisms of Neurodegeneration and Clearance: From Caspases to Chemokines.
Sokolowski, Jennifer, Neuroscience - Graduate School of Arts and Sciences, University of Virginia
Mandell, James, Department of Pathology, University of Virginia
Neuronal death and axon degeneration occur during brain development, during physiological turnover of neurons, and after injury. Degeneration is not a passive phenomenon, but an ordered, active process. Apoptosis, or programmed cell death, leads to activation of proteolytic enzymes known as caspases which are responsible for degrading proteins and preparing the apoptotic cell for clearance. Degeneration is not a passive phenomenon, but an ordered, active process. Apoptosis, or programmed cell death, leads to activation of proteolytic enzymes known as caspases which are responsible for degrading proteins and preparing the apoptotic cell for clearance. We studied the features of axon degeneration and confirmed that apoptotic machinery is involved. We detected caspase-mediated cytoskeletal degradation a) in vitro, in neuronal cultures induced to undergo axonal degeneration via nerve growth factor deprivation, b) in vivo, after alcohol-induced apoptosis as well as during developmental pruning and physiological turnover of neurons, and c) in degenerating neurites in human hypoxic-ischemic injury. In addition to examining degeneration, we also studied mechanisms involved in clearance. We showed that the chemokine fractalkine is released after alcohol-induced apoptosis and that fractalkine modulates the recruitment of microglia to promote clearance of apoptotic cells. In mice lacking fractalkine or its receptor, CX3CR1, injury leads to increased apoptotic debris and altered cytokine production. We also studied an engulfment receptor, Brain-specific angiogenesis inhibitor-1 (BAI1), to determine whether it plays a role in clearance in the brain. Immunolocalization data and analysis of the BAI1-deficient mouse suggested that while it may subserve astrocytic engulfment, it is unlikely to play a critical role in microglial engulfment. We found BAI1 was predominantly neuronal and localized to neuropil, suggesting a synaptic function, and we found no evidence of a defect in clearance in the BAI1-knockout mouse after alcohol-induced apoptosis. Further work should aim to identify receptors required for glial engulfment during apoptotic cell clearance in the brain.
PHD (Doctor of Philosophy)
apoptosis, axon degeneration, fractalkine, brain-specific angiogenesis inhibitor 1, phagocytosis, neurodegeneration
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