Quercetin Ameliorates the Astrocyte Cytoxicity Induced By HIV-1 gp120 Via Promoting Insoluble Stress Granules Disassembly

Backgrounds:

HIV-associated neurocognitive disorders (HAND) are a group of syndromes characterized by neuropathy, dementia, and neural cognitive impairment in HIV-1 infected individuals, and the specific mechanism is still under shadow. Insoluble protein complexes play an important role in the pathological process of neurodegenerative diseases. Under stress conditions, eukaryotic cells generate the droplets form complexes, called stress granules (SGs), taking G3BP1 protein as the core, raising mRNA and proteins, and when exist chronically SGs will transform into harmful insoluble SGs, which have been proved to be closely related to the occurrence of neurodegenerative diseases. In current study, there has no report on HAND caused by SGs. Quercetin (QC), a kind of natural flavonoids in plants, has been reported possessing neural protective effect in the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. In this study, we aimed to investigate the changes of SGs formation in the brain tissue of HIV-1 gp120 transgenic mice (Gp120 tgm, a stable mice model for simulating the HAND), and the effect of QC on the disassembly of SGs in HAND models.

Methods:

Six Gp120 tgm were involved and randomly divided into Gp120 group (n=3) and QC group (n=3). The same genetic background C57BL/6 mice were included into the wild-type group (n=3). Mice in QC group were intervened with 50 mg/kg QC suspension for 30 days by gavage, the others group were fed with 0.9% normal saline by gavage. At the end of the Morris water maze behavioral experiment, serum and brain tissue were collected. The formation of SGs in brain tissue took immunohistochemical technique in the detection. On the other hand, immunofluorescence was applied to detect the SGs formation situation in primary astrocytes induced with HIV-1 gp120 or QC in vitro. The expression level of G3BP1 protein, the core protein of SGs, in brain tissues and primary astrocytes was detected by Western blot.

Results:

Compared to wile-type group, Gp120 group took more time to locate the platform and less platform through number in Morris water maze behavioral experiment, while after intervened with QC for 30 days, QC group spent less time and distance in locating platform, and the number of underwater platform passing through increased significantly. In the immunohistochemical sections of each group of experimental animals, the rate of G3BP1 positive cell was significant increased in Gp120 group (p<0.05), and was improved after the intervention of QC (p<0.05). The expression of G3BP1 was significantly upregulated in the brain tissues of Gp120 tgm (p<0.05) and decreased after QC intervention (p<0.05). In vitro experiment, the rate of G3BP1 positive cells and the intensity of fluorescence of G3BP1 were elevated in primary astrocytes after HIV-1 gp120 stimulation (p<0.05), and both decreased after the treatment of QC (p<0.05). Western blot showed the same results as the in vivo experiment. HIV-1 gp120 up-regulated the expression of G3BP1 in primary astrocytes, while treated with QC returned to normal level (p<0.05). In total, these results suggested that treatment with QC ameliorates neurocognitive impairments via promoting the disassembly of SGs in Gp120 tgm.

Conclusions:

A significant increase of SGs formation has been proved in the brain tissue of Gp120 tgm, and the same results is obtained in an in vitro primary astrocytes model. QC treatment is able to significantly reduce the number of SGs formation both in the brain tissue of Gp120 tgm and in primary astrocytes induced with HIV-1 gp120. In addition, QC is capable to significantly improve the neural cognitive impairment of Gp120 tgm in the gut-blood-brain way as a dietary supplement. (Acknowledgements: This study was supported by National Natural Science Foundation of Guangdong, China, No. 2024A1515010606 to H. Cao and Grant from School of Public Health of Southern Medical University, China, Grant No. GW202329 to H. Cao; Corresponding author: Hong Cao, gzhcao@smu.edu.cn)

No relevant conflicts of interest to declare.