Loss of neurons in the frontal cortex in AIDS brains

Ketzler, S.; Weis, Serge; Haug, H; Budka, Herbert

doi:10.1007/bf00294228

Cited by 342 publications

(105 citation statements)

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“…Previous studies have documented neuronal loss in both demented and nondemented AIDS patients (19,20). As many as 50% of AIDS patients with dementia do not have histopathologic evidence of HIV-1 encephalitis, particularly patients with milder symptoms (4, 7).…”

Section: Discussionmentioning

confidence: 99%

“…The neuropathology of HIV-1 infection includes brain atrophy, demyelination, reactive astrocytosis, microglial nodules, multinucleated giant cells, and evidence of abnormal blood-brain-barrier permeability (3)(4)(5)(14)(15)(16)(17)(18). Neuronal loss, dendritic pathology, and decreased synaptic density have also been documented (19)(20)(21)(22). Affected brain regions include the basal ganglia, subcortical white matter, and cerebral cortex (1,4,14,15).…”

Section: Introductionmentioning

confidence: 99%

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Apoptosis induced by HIV-1 infection of the central nervous system.

et al. 1996

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Apoptosis plays a role in AIDS pathogenesis in the immune system, but its role in HIV-1-induced neurological disease is unknown. In this study, we examine apoptosis induced by HIV-1 infection of the central nervous system (CNS) in an in vitro model and in brain tissue from AIDS patients. HIV-1 infection of primary brain cultures induced apoptosis in neurons and astrocytes in vitro as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and propidium iodide staining and by electron microscopy. Apoptosis was not significantly induced until 1-2 wk after the time of peak virus production, suggesting induction by soluble factors rather than by direct viral infection. Apoptosis of neurons and astrocytes was also detected in brain tissue from 10/11 AIDS patients, including 5/5 patients with HIV-1 dementia and 4/5 nondemented patients. In addition, endothelial cell apoptosis was frequently detected in the brain of AIDS patients and was confirmed by electron microscopy. Most of the apoptotic cells were not localized adjacent to HIV-1-infected cells, providing further evidence for induction by soluble factors. In six non-AIDS control patients with normal brain, apoptotic cells were absent or limited to rare astrocytes. However, TUNEL-positive neurons and astrocytes were frequently detected in seven patients with Alzheimer's disease or abundant senile plaques. These studies suggest that apoptosis is a mechanism of CNS injury in AIDS which is likely to be induced by soluble factors. The apoptosis of endothelial cells in the CNS raises the possibility that some of these factors may be blood-derived. (

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Apoptosis induced by HIV-1 infection of the central nervous system.

et al. 1996

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“…The development of neurological disease in individuals infected with human immunode®ciency virus (HIV) is the culmination of a long history of viral interactions with the brain which slowly kill selected cortical and subcortical neurons (Wiley et al, 1991;Ketzler et al, 1990;Weis et al, 1993;Gray et al, 1991). Data from both human and animal studies suggest that the neural disease, is progressive and that it may begin in the asymptomatic stage, long before the development of AIDS (Lendhardt et al, 1988;Elovaara et al, 1990;Meeker et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Neurotoxicity of CSF from HIV-infected humans

et al. 1999

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Approximately 15 ± 20% of individuals infected with the human immunode®ciency virus will develop severe neurological disease. This may be due in part to virus-induced release of a number of putative neurotoxins. However, there is little information to predict which individuals will progress to dementia or the precise mechanisms that drive pathogenesis. In an effort to identify early markers of neurological disease progression we used an in vitro bioassay with rat cortical neurons to test for the presence of toxins in CSF from 40 HIVinfected humans with mild, minimal or no neurological disease. A subset of HIV-infected individuals was found to have signi®cant toxic activity in CSF indicating that toxic factors may be circulating prior to the development of dementia. The toxicity was concentration dependent and due to a factor with a molecular mass of less than 30 kDa. Only a small proportion of the cell death appeared to be due to apoptosis. Neuronal toxicity was associated with a gradual accumulation of intracellular calcium in a subset of cortical neurons over a period of 1 ± 2 h and in the absence of a signi®cant acute response. Individuals with both high viral burden and high CSF toxicity were signi®cantly more likely to have neurological symptoms. These initial analyses indicate that toxic factors are present in the CSF of HIV-infected patients that could serve as useful markers of neurological disease progression and provide insights into pathogenic mechanisms in vivo.

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“…Manifestations of ADC are progressive cognitive, motor, and behavioral dysfunctions that have been linked to the persistence of HIV-1 infections in the CNS and are mainly found in CD4-positive (CD4+) microglial cells and circulating macrophages (Budka, 1991;Fauci, 1988;Jordan et al, 1991;Ketzler et al, 1990;Liu et al, 1990;Maddon et al, 1986;McArthur, 1987;Merrill and Chen, 1991;Price et al, 1988). However, in the absence of CD4 molecules on the cell membrane of the majority of brain cells and in the light of the paucity of direct evidence for HIV infection of neurons and glial cells it has been suggested that the HIV-associated degenerative neurological abnormalities are the result of indirect mechanisms mediated by soluble factors of viral or cellular origin (Brenneman et a/., 1988;Dreyer et al, 1990;Giulian et al, 1990;Kaiser et al, 1990;Pulliam et al, 1991;Wahl et al, 1991 ).…”

Section: Introductionmentioning

confidence: 99%

HIV-1 gp120 receptor on CD4-negative brain cells activates a tyrosine kinase

Schneider-Schaulies¹,

Schneider‐Schaulies²,

Brinkmann³

et al. 1992

Virology

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Human immunodeficiency virus (HIV-1) infection in the human brain Ieads to characteristic neuropathological changes, which may result indirectly from interactions of the envelope glycoprotein gp 120 with neurons and/or glial cells. We therefore investigated the binding of recombinant gp120 (rgp120) to human neural cells and its effect on int~acellular.s.ignallin~. Herewe pre~ent evidence that rgp120, besides binding to galactocerebroside or galactosyl-sulfatlde, spec1f1cally bmds to a protem receptor of a relative molecular mass of approximately 180,000 Da (180 kDa) pre~ent. on the CD4-negative glioma cells D-54, but not on Molt4 T lymphocytes. Binding of rgp120 to this receptor rap1dly 1nduced a tyrosine-specific protein kinase activity leading to tyrosine phosphorylation of 130-and 115-kDa p~oteins. The c~ncentration of intracellular calciumwas not affected by rgp120 in these cells. Our data suggest a novel Signal transduc1ng HIV-1 gp120 receptor on CD4-negative glial cells, which may contribute to the neuropathological changes observed in HIV-1-infected brains.

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Loss of neurons in the frontal cortex in AIDS brains

Cited by 342 publications

References 10 publications

Apoptosis induced by HIV-1 infection of the central nervous system.

Apoptosis induced by HIV-1 infection of the central nervous system.

Neurotoxicity of CSF from HIV-infected humans

HIV-1 gp120 receptor on CD4-negative brain cells activates a tyrosine kinase

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