In vivo proton magnetic resonance spectroscopy detection of metabolite abnormalities in aged Tat-transgenic mouse brain

Abstract

Most individuals living with HIV in the USA are over 45 years old and are vulnerable to the combined effects of HIV and aging. Antiretroviral therapies reduce HIV morbidity and mortality but do not prevent HIV trans-activator of transcription (Tat) protein expression or development of HIV-associated neurocognitive disorder (HAND), which may be caused by Tat. Tattransgenic (Tat-tg) mice are used to study Tat's effects, typically after transgene induction with doxycycline. However, uninduced Tat-tg mice experience transgene leak and model aspects of HAND when aged, including neuroinflammation. We used in vivo 9.4-tesla proton magnetic resonance spectroscopy to compare neurochemistry in aged versus young female and male uninduced Tat-tg mice. Aged Tat-tg mice demonstrated measurable tat mRNA brain expression and had lower medial prefrontal cortex (MPFC) GABA, glutamate, and taurine levels and lower striatal GABA and taurine levels. Females had lower MPFC glutathione and taurine and lower striatal taurine levels. Brain testosterone levels were negatively correlated with age in aged males but not females. Aged mice had cortical abnormalities not previously reported in aged wild-type mice including lower MPFC GABA and taurine levels. As glutathione and taurine levels reflect inflammation and oxidative stress, our data suggest that Tat may exacerbate these processes in aged Tat-tg mice. However, additional studies in controls not expressing Tat are needed to confirm this point and to deconvolve individual effects of age and Tat expression. Sex steroid hormone supplements, which counter climacteric effects, increase taurine levels, and reduce inflammation and oxidative stress, could attenuate some of the brain abnormalities we identified in aged Tat-tg mice.

HIV-1 Tat Protein Promotes Neuroendocrine Dysfunction Concurrent with the Potentiation of Oxycodone’s Psychomotor Effects in Female Mice

“…Briefly, mice expressed the Tat 1-86 protein via conditional, GFAP-relegated expression under regulation of a reverse tetracycline-controlled transactivating (rtTA) transcription factor. We and others have previously confirmed mRNA expression of tat in the brain and spinal cord of these mice [44][45][46] and include confirmation in the present tissues via quantitative real-time PCR (see Supplemental Data, Figure S1). Tat(−) control mice lacked the tat transgene but did express the rtTA transcription factor [47].…”

Age-related neuroendocrine, cognitive, and behavioral co-morbidities are promoted by HIV-1 Tat expression in male mice

“…Together, these data support the notion that maintaining the endocrine milieu of the CNS promotes resilience to neurodegenerative insults, including those associated with older age. In support, we recently found that T declines with age in the medial prefrontal cortex and striatum of Tat-expressing transgenic mice, concurrent with decrements in excitatory and inhibitory neurotransmitters as well as endogenous antioxidants detected with magnetic resonance spectroscopy [ 89 ]. These findings are consistent with clinical observations of cognitive impairment [ 90 ] that occurred in parallel with cerebral metabolic disturbances including a reduction of N-acetyl aspartate and an increase of choline and myoinositol, markers of inflammation, in HIV + patients [ 29 , 90 , 91 ].…”

The role of sex and ovarian hormones in hippocampal damage and cognitive deficits induced by chronic exposure to hypobaric hypoxia

“…In this study, the serum testosterone level of the male CHH group was lower than the male control group, and the serum estradiol level of the female CHH group was higher than the female control group, which was consistent with the previous reports ( Liu et al, 2020 ; Pooja et al, 2020 ). Estrogen has antioxidant ( Yazğan et al, 2016 ; Paris et al, 2021 ), anti-inflammatory ( Fallarino et al, 2010 ; Siani et al, 2017 ), and neuroprotective effects ( Cipolla et al, 2009 ; Robison et al, 2019 ), which was been widely reported. Although it has been reported in recent years that androgens also have anti-inflammatory ( Mohamad et al, 2019 ; Babcock et al, 2022 ) and antioxidant ( Ahlbom et al, 2001 ) effects, however, the protective effect of testosterone has a dichotomous effect.…”