Title

TAARgeting Astrogliosis and Mitochondrial Dysfunction during METH Exposure and HIV-relevant Neuroinflammation

Date of Award

12-1-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Field of Study

Biomedical Sciences

Department

Graduate School of Biomedical Sciences

First Advisor

Anuja Ghorpade

Second Advisor

Robert J. Wordinger

Third Advisor

Rance E. Berg

Abstract

As a popular psychostimulant, methamphetamine (METH) use leads to long-lasting, strong euphoric effects. METH exacerbates the severity and onset of HIV-associated neurocognitive disorders (HAND), which affect 30-70% of the 37.6 million people globally infected with HIV. Most neurodegenerative diseases share neuroinflammation as a common pathogenic mechanism. Neuroinflammation, HIV and METH dysregulate a wide range of brain functions including neuronal signaling, glial activation, viral infection, oxidative stress and excitotoxicity. Since neuroglia determine the outcome of neurological disease, we investigate the mechanisms regulating astrocyte-mediated neurotoxicity in the context of METH and HIV comorbidity. To these ends, we examined the expression, localization and function of the novel METH astrocyte receptor, trace amine associated receptor 1 (TAAR1) in an extended METH in vitro model, which mimics chronic residual METH concentrations between binges, and HIV-associated activation. In our model, TAAR1 levels and localization to the endoplasmic reticulum and plasma membranes increased with METH and HIV-induced astrogliosis. Extended physiological METH exposure led to augmented calcium flux, a mechanism known to mediate ER and mitochondrial, and oxidative stress. METH induced dysregulation of astrocyte mitochondrial morphology by elevating mitofusin expression and inhibitory phosphorylation of dynamin-related protein-1. While METH decreased oxygen consumption and ATP levels during acute exposure, chronic treatment significantly enhanced both. Together, these changes increased expression of antioxidant proteins, augmenting the astrocyte’s oxidative capacity, but also oxidative damage. METH and HIV activation impaired excitatory amino acid transporter 2 (EAAT2) expression and activity, which were recovered by inhibition of TAAR1 with EPPTB, a TAAR1 selective antagonist. Together, these data highlight several mechanisms regulating METH/HIV-induced, astroglia-mediated neurotoxicity and the potential for astrocyte targeted intervention via TAAR1 during chronic disease. We propose that equilibrium between agonism of neuronal TAAR1 and antagonism of astrocyte TAAR1 will need to be further investigated to balance the neuroprotective benefits of TAAR1 targeting drugs in the CNS during HIV and METH comorbidity.

Comments

Kathleen Borgmann, TAARgeting Astrogliosis and Mitochondrial Dysfunction during METH Exposure and HIV-relevant Neuroinflammation. Doctor of Philosophy (Biomedical Sciences), October 2017, 177 pp., 8 tables, 21 illustrations, bibliography, 624 titles. Available worldwide December 2018.

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