Neurocognitive decline and dysregulation of Astrocyte-TIMP-1 in a Tat-transgenic mouse model

Purpose: Despite antiretroviral therapy, HIV-associated neurocognitive disorders (HAND) persist in 60-70% of patients. In the brain, HIV-1 non-productively infects astrocytes, which produce and release HIV-1 proteins such as transactivator of transcription (Tat). Tat induces neuronal death and inflammation by direct and indirect mechanisms. During HAND, elevated matrix metalloproteinases (MMPs) aid ECM breakdown facilitating disease progression; whereas, tissue inhibitors of MMPs (TIMPs) impede their activity. Astrocyte TIMP-1 is an inducible protein and its neuroprotective effects have been shown. Astrocyte TIMP-1 expression increases with acute neuroinflammation in vitro, but its levels are reduced during chronic inflammatory brain diseases; indicative of a concomitant loss of TIMP-1 mediated neuroprotection. However, little is known about Tat regulation of astrocyte TIMP-1 expression. We hypothesize that HIV-1 Tat downregulates astrocyte TIMP-1 and induces inflammatory changes that contribute to neurocognitive decline. Methods: A doxycycline-inducible, glial fibrillary acidic protein (GFAP) promoter-restricted HIV-1 Tat mouse model (GT-Tg) was used to investigate astrocyte associated disease mechanisms. Neurocognitive decline was assessed using a battery of behavior tests in GT-Tg and wild-type (WT) mice. Subsequently, mouse brains were harvested to evaluate gene and protein expression. Results: GT-Tg mice had higher anxiety and lower initiation latency in elevated plus maze and locomotor activity tests, respectively. While GT-Tg mice swam faster in Morris water maze, latency and pathlength were comparable to WT. Discriminated reversal test and novel object recognition did not differ significantly between GT-Tg and WT mice. Although TIMP-1 gene expression was elevated in GT-Tg verses WT mice, it negatively correlated with Tat expression consistent with human astrocytes chronic responses. Gene and protein expression for other inflammatory biomarkers and GFAP were evaluated, and correlated with Tat expression. Conclusions: Collectively, our data from GT-Tg mouse model confirmed that TIMP-1 dysregulation is associated with neurocognitive decline in the context of HAND suggesting replenishing TIMP-1 levels could be used as a novel therapeutic option.