Glia-mediated mechanisms of HIV-1-gp120-induced Synaptic Degeneration
| dc.creator | Ru, Wenjuan | |
| dc.creator.orcid | 0000-0001-5065-027X | |
| dc.date.accessioned | 2021-04-21T16:07:36Z | |
| dc.date.created | 2019-05 | |
| dc.date.submitted | May 2019 | |
| dc.date.updated | 2021-04-21T16:07:37Z | |
| dc.description.abstract | HIV-1 infection of the nervous system causes various neurologic diseases. Synaptic degeneration is a critical underlying neurological pathology. However, the mechanism by which HIV-1 causes synaptic degeneration is unclear. In this dissertation, we tested the role of HIV- envelope protein gp120 in pathogenesis of degeneration both in the spinal cord and the cortex. In the spinal cord, gp120 exposure caused synaptic degeneration. Because gp120 induced microglial activation, we further tested the hypothesis that microglia contribute to gp120-induced synaptic degeneration. We found that blockage of microglial activation abolished the synapse loss induced by gp120. Fractalkine (FKN; a.k.a.CX3C ligand-1 or CX3CL1), a microglia-activation chemokine that is specifically expressed in neurons, was up-regulated in response to gp120 stimulation. Knockout (KO) of the FKN receptor CX3CR1, which is specifically expressed on microglia, protected synapses from gp120-induced degeneration. These results indicate that the neuron-to-microglia intercellular FKN/CX3CR1 signaling is critical for gp120-induced synaptic degeneration. To elucidate the molecular mechanism that controls this intercellular signaling, we tested the role of the Wnt3a/β-catenin pathway in regulating FKN expression. We found that inhibition of this pathway blocked both the gp120-induced FKN up-regulation and the synaptic degeneration. We also found that gp120 stimulates FKN expression, which is mediated by Wnt3a/β-catenin signaling, via NMDA receptor activation. These findings collectively suggest that HIV-1 gp120 induces synapse degeneration via microglial activation regulated by the Wnt3a/β-catenin/ FKN pathway. Significant synaptic degeneration was observed in the cortex of gp120 transgenic (Tg) mice. Our data suggest that glial phagocytosis greatly contributed to gp120-induced synaptic loss. Interestingly, microglia predominately engulf and eliminate pre-synaptic structures, while reactive astrocytes act predominantly at the postsynaptic compartment. Ablation of microglia protected pre-synaptic elements from gp120-induced elimination. Furthermore, the MerTk signal pathway contributed to gp120- induced microglial phagocytosis of pre-synaptic terminal but was not involved in astrocytic phagocytosis of post-synaptic terminal. Our studies reveal critical roles microglial and astrocytic phagocytosis in HIV-associated synaptic degeneration. | |
| dc.format.mimetype | application/pdf | |
| dc.identifier.uri | https://hdl.handle.net/2152.3/11313 | |
| dc.subject | Synapse | |
| dc.subject | Microglia | |
| dc.subject | Astrocytes | |
| dc.subject | Degeneration | |
| dc.subject | Phagocytosis | |
| dc.title | Glia-mediated mechanisms of HIV-1-gp120-induced Synaptic Degeneration | |
| dc.type | Thesis | |
| dc.type.material | text | |
| local.embargo.lift | 2021-05-01 | |
| local.embargo.terms | 2021-05-01 | |
| thesis.degree.department | Neuroscience | |
| thesis.degree.grantor | The University of Texas Medical Branch at Galveston | |
| thesis.degree.level | Doctoral | |
| thesis.degree.name | Neuroscience (Doctoral) |