Characterization of neuropathology in the HIV-1 transgenic rat at different ages

Abstract

The transgenic HIV-1 rat (Tg) is a commonly used neuroHIV model with documented neurologic/behavioral deficits. Using immunofluorescent staining of the Tg brain, we found astrocytic dysfunction/damage, as well as dopaminergic neuronal loss/dysfunction, both of which worsening significantly in the striatum with age. We saw mild microglial activation in young Tg brains, but this decreased with age. There were no differences in neurogenesis potential suggesting a neurodegenerative rather than a neurodevelopmental process. Gp120 CSF levels exceeded serum gp120 levels in some animals, suggesting local viral protein production in the brain. Further probing of the pathophysiology underlying astrocytic injury in this model is warranted.

Keywords: Astrocytic loss; HIV-1 transgenic rat; Neuro-HIV; Neuropathology; Neurotoxicity; Viral proteins.

Fig. 1

(A) Brain sections of one 3-month-old WT (upper row) and two age-matched Tg rats (middle and lower rows), encompassing parts of the cortex (CX), striatum (ST), and corpus callosum (CC) stained with NeuN (green) and GFAP (yellow) (first and second columns: 8.4× magnification, scale bar: 500µm; third and fourth columns: 50× magnification, scale bar: 100µm). (B) Brain sections of one 7-month-old WT (upper row) and two age-matched Tg rats (middle and lower rows), encompassing parts of the cortex (CX), striatum (ST), and corpus callosum (CC) stained with NeuN (green) and GFAP (yellow) (first and second columns: 8.4× magnification, scale bar: 500µm; third and fourth columns: 50× magnification, scale bar: 100µm). Decreased GFAP staining is seen in at least one of the two 3 month-old Tg animals (lower row) however is more obvious in the 7 month-old rats.

Fig. 1

(A) Brain sections of one 3-month-old WT (upper row) and two age-matched Tg rats (middle and lower rows), encompassing parts of the cortex (CX), striatum (ST), and corpus callosum (CC) stained with NeuN (green) and GFAP (yellow) (first and second columns: 8.4× magnification, scale bar: 500µm; third and fourth columns: 50× magnification, scale bar: 100µm). (B) Brain sections of one 7-month-old WT (upper row) and two age-matched Tg rats (middle and lower rows), encompassing parts of the cortex (CX), striatum (ST), and corpus callosum (CC) stained with NeuN (green) and GFAP (yellow) (first and second columns: 8.4× magnification, scale bar: 500µm; third and fourth columns: 50× magnification, scale bar: 100µm). Decreased GFAP staining is seen in at least one of the two 3 month-old Tg animals (lower row) however is more obvious in the 7 month-old rats.

Fig. 2

Brain sections of 7-month-old WT (upper row) and age-matched Tg (lower row) rats, at the level of the striatum (magnification 100×, Scale bar: 50µm). Decreased GFAP staining is seen in the Tg compared to WT rat however Iba1 staining appears comparable.

Fig. 3

PCNA staining (yellow) in the subventricular zone (SVZ) in 1 month-old WT and Tg rat brains is comparable suggesting preserved neurogenesis in the Tg rat despite the presence of the transgene (magnification 100×, Scale bar: 50µm). Additional stains include DAPI (gray) and NeuN (green).

Fig. 4

Relative mRNA expression levels of GFAP, Iba1 and CD11b in striatal (ST) and hippocampal (HC) tissues derived from 1 month-old (n= 3) and 8–9 month-old (n=5) Tg and WT rats. Although GFAP expression was generally lower in the Tg compared to WT rats, those differences were not statistically significant in either age group. Values for CD11b are re-plotted separately using a different scale for better appreciation. Error bars represent standard deviation values.