Award Date

May 2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Psychology

First Committee Member

Jefferson Kinney

Second Committee Member

James Hyman

Third Committee Member

Rochelle Hines

Fourth Committee Member

Merrill Landers

Number of Pages

120

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and distinct neuropathological hallmarks, including amyloid beta plaques and neurofibrillary tau tangles (NFT). Although the etiology remains to be discovered, several risk factors exist that significantly contribute to developing AD. Diabetes is one of the major risk factors associated with AD and is characterized by disrupted insulin signaling that may contribute to or exacerbate AD pathologies. Furthermore, both disorders result in increased neuroinflammation. Considerable evidence has demonstrated that a chronic inflammatory response, in particular chronic microglia activation, promotes A production as well as the hyperphosphorylation of tau through the sustained release and increased levels of several pro-inflammatory cytokines. These data make understanding the mechanisms driving the inflammatory response and treatment of the inflammation an important target in AD research. In addition to aberrant microglia functioning, the loss of a number of aspects of GABAergic signaling, including GABAB receptors, have been reported in clinical AD populations and animal models of AD. As microglia express functional GABAB receptors and activation on microglia appear to reduce their activity, GABA signaling may result in a decrease in pro-inflammatory cytokine production. Therefore, the purpose of this study is to investigate the role of GABAB in neuroinflammation encompassing to AD pathogenesis using a non-transgenic animal model related to diabetes. Using a low-dose schedule of streptozotocin (STZ) administration to induce a sustained hyperglycemic state, we treated with animals with a GABAB receptor agonist (baclofen) to reduce activated microglia and pro-inflammatory effects. We found that STZ administration led to significantly increased blood glucose levels, memory impairments in the novel object recognition task, hyperphosphorylated tau, increased activated microglia, and pro-inflammatory cytokines. Treatment with baclofen ameliorated the above changes induced by STZ. Therefore, GABAB receptors play a role in modulating microglia function and neuroinflammation.

Keywords

Alzheimer's; Diabetes; GABAB; Streptozotocin; Tau

Disciplines

Medical Neurobiology | Neuroscience and Neurobiology | Neurosciences

Language

English


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