Correlation between neurological progression and astrocyte apoptosis in HIV-associated dementia

Abstract

The pathogenesis of HIV-associated dementia (HIVD) has been postulated to be due to the indirect effects of HIV infection, including the aberrant central nervous system production of cytokines and other neurotoxins. A correlation between the severity of dementia and production of neurotoxins in HIVD has been demonstrated. We have previously identified nonproductive HIV infection of astrocytes. Because astrocytes participate in the inactivation of neurotoxins, we hypothesize that HIV nonproductive infection of astrocytes may lead to an environment in which there is a significant level of astrocyte apoptosis and a consequent increase in the levels of neurotoxins and that this results in more rapidly progressing dementia. Postmortem brain tissue was examined from clinically well-characterized HIV-positive demented patients, HIV-positive nondemented patients, and HIV-seronegative nondemented control subjects. The HIVD group was further categorized into subjects with rapid and those with slow progression of dementia. Tissue was paraformaldehyde fixed and paraffin embedded, and 6-microm sections from the basal ganglia and mid-frontal gyrus were processed to detect apoptosis by in situ transferase dUTP nick end labeling. Astrocytes were co-localized using immunohistochemical techniques. In situ polymerase chain reaction (PCR) techniques were utilized to detect HIV DNA in astrocytes. The density of apoptotic astrocytes was significantly greater in the HIV-positive groups than in the HIV-negative group (p < 0.01). The HIVD rapid progressors had a significantly greater number of apoptotic astrocytes in the basal ganglia than did the HIVD slow progressors (p < 0.05). In addition, there were a greater number of HIV DNA-positive astrocytes, as demonstrated by in situ PCR, in the HIVD rapid progressors than in the slow progressor and HIV-nondemented groups. These data suggest that there is an increased rate of astrocyte loss in the subjects with rapidly progressive dementia, in association with an increased number of HIV DNA-positive astrocytes. The results emphasize the importance of understanding more completely the role of HIV infection of astrocytes in the neuropathogenesis of HIVD.

3D pattern of brain atrophy in HIV/AIDS visualized using tensor-based morphometry

“…The blood-brain barrier breaks down and HIVinduced cytokines and neurotoxins are produced, causing dendritic simplification and neuronal loss. Regionally, central white matter and deep gray matter structures -such as the basal ganglia, thalamus, and brainstem -are particularly vulnerable to atrophy (Budka et al, 1987;Price et al, 1988;Thompson et al, 2001;Gray et al, 2003;Bell, 2004;McArthur et al, 2005). In a recent MRI study, we found selective cortical thinning in primary sensorimotor, premotor, and visual areas in AIDS .…”

Astrocytes in Alzheimer's Disease

“…140 Both astrogliosis and astroglial atrophy were observed in immunodeficiency virus-1 (HIV-1) associated dementia, in which astrogliosis in the initial phase is followed by significant astro-cytic death; the loss of astrocytes correlates with the severity of cognitive impairments. 141,142 Astrocytes can also be a target for tau pathololgy, and specific expression of tau protein in astroglial cells can trigger agedependent neurodegeneration. 143,144 Impairment of astroglia is also involved in pathogenesis of Wernicke encephalopathy, which is associated with a very substantial reduction in expression of astroglial glutamate transporters; this results in compromised clearance of glutamate with subsequent neuronal death through excitotoxicity.…”

Astroglia in dementia and Alzheimer's disease

“…45,46 At the same time, however, HAD also leads to a prominent apoptotic death of astrocytes especially in the patients with rapidly progressing cognitive deficits. 47 …”