Interruption of neuron-microglia bidirectional communication to modulate cofilin:actin rod formation
Date
2022
Authors
Zoller, Maia, author
Bamburg, James, advisor
Chanda, Soham, committee member
Zabel, Mark, committee member
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Abstract
Immune responses in the central nervous system are mediated by microglia, whose responses to CNS threats can be replicated in vitro to study the role of microglia in the onset, progression, and treatment of neurodegenerative diseases. Previous work has identified a pathway common to neurodegenerative diseases such as Alzheimer's Disease, Parkinson's Disease, and HIV-Associated Neurocognitive Dementia in which the actin-severing protein, cofilin, forms a 1:1 bundle with actin making rod-shaped inclusions (rods) that can be found in the dendrites and axons of neuronal cells. This thesis focuses on developing methods for examining the role of primary microglia, activated by different factors, to secrete rod-inducing chemokines/cytokines or directly attacking neurons leading to neuronal death. Understanding both of these mechanisms is important in study of neuroinflammation and disease progression. Hemin, a hemoglobin metabolite, and alarmin, S100B, a astrocyte secreted, calcium binding protein, protein, were used to model the environment of intracerebral hemorrhage and general neuroinflammation respectively. Preliminary experimental results suggest blockage of actin-rod inducing signaling pathways via CXCR4/CCR5 receptor antagonist improves neuronal survival to both microglia conditioned medium and direct exposure the microglia-activating hemin or S100B. Further studies are in progress to obtain sufficient statistical data to verify these results.
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Subject
chemokines
CXCR4
neuroinflammation
cofilin:actin rods
Alzheimer's disease
microglia