Expression of excitatory amino acid transporter-1 (EAAT-1) in brain macrophages and microglia of patients with prion diseases.

The mechanisms of neuronal apoptosis in prion diseases are unclear. Experimental studies suggest that it may result from 2 associated mechanisms: glutamate-mediated excitotoxicity and oxidative stress. Recent studies showed that activated macrophages/microglia (AMM) express excitatory amino acid transporters (EAATs) in HIV infection, suggesting that they may play a neuroprotective role by clearing extra-cellular glutamate and producing anti-oxidant glutathione. In order to test this hypothesis in prion diseases, samples from cerebral cortex, striatum, thalamus, and cerebellum from 14 patients with Creutzfeldt-Jakob disease (8 sporadic, 2 familial, 2 iatrogenic, and 2 variant), and 4 with fatal familial insomnia (3 homozygous Met/Met at codon 129 of the PRNP gene, 1 heterozygous Met/Val), and 3 controls were immunostained for EAAT-1, GFAP, HLA-DR, CD68, IL-1, caspase 3, and PrP. In prion diseases, EAAT-1 immunopositivity was found in affected areas. Only AMM, interstitial, perivascular, perineuronal (sometimes around apoptotic neurons), or close to reactive astrocytes, expressed EAAT-1. Astrocyte EAAT-1 expression was scarcely detectable in controls and was not detected in prion disease cases. The proportion of AMM expressing EAAT-1 did not correlate with the severity of neuronal apoptosis, spongiosis, astrocytosis, microgliosis, or PrP deposition, but only with disease duration. Occasional EAAT-1 expressing AMM were found in patients with short survival, whereas diffuse EAAT-1 expression by AMM was observed in cases with long survival (24 to 33 months) that most often were heterozygous for Met/Val at codon 129 of the PRNP gene. Our findings suggest that AMM may develop a partial neuroprotective function in long-lasting prion diseases, although it does not seem to efficiently prevent neurological and neuropathological deterioration. Whether this neuroprotective function of microglia is the cause or the effect of longer survival needs to be clarified.

[Neurotoxicity and neuroprotection, two aspects of microglial activation in human immunodeficiency virus (HIV) infection]. / Neurotoxicité et neuroprotection, les deux facettes de l'activation microgliale au cours de l'infection par le virus de l'immunodéficience humaine (VIH).

Microglial cells and macrophages are the only cells within the central nervous system, in which productive HIV infection has been unquestionably demonstrated. Those cells play a key role in the origin of the neuronal dysfunction underlying HIV-related cognitive disorders. The neurotoxicity of the cells is both direct, related to HIV proteins, and indirect, through the release by activated macrophages and microglial cells (AMM) of multiple neurotoxic factors. The mechanisms of neuronal damage, the final irreversible stage of which is neuronal apoptosis, are only partly understood but appear to involve oxidative stress and glutamate-receptor mediated toxicity. On the other hand, recent experimental in vitro and in vivo studies, and neuropathological studies in HIV infected patients at different stages of the disease, tend to show that AMM express excitatory amino acid transporters (EAAT) suggesting that in addition to their neurotoxic properties, they also have a neuroprotective role by clearing extra-cellular glutamate and producing antioxidant glutathione. This neuroprotective role could counteract, at least in the early stages of the disease, the neurotoxicity of AMM explaining the discrepancy between the conspicuous microglial activation at that stage and the absence of cognitive disorder, neuronal loss and neuronal apoptosis. It could also explain the regression of the cognitive disorders in some patients who received highly active antiretroviral treatment.

Regulated expression of sodium-dependent glutamate transporters and synthetase: a neuroprotective role for activated microglia and macrophages in HIV infection?

It is now widely accepted that neuronal damage in HIV infection results mainly from microglial activation and involves apoptosis, oxidative stress and glutamate-mediated neurotoxicity. Glutamate toxicity acts via 2 distinct pathways: an excitotoxic one in which glutamate receptors are hyperactivated, and an oxidative one in which cystine uptake is inhibited, resulting in glutathione depletion and oxidative stress. A number of studies show that astrocytes normally take up glutamate, keeping extracellular glutamate concentration low in the brain and preventing excitotoxicity. This action is inhibited in HIV infection, probably due to the effects of inflammatory mediators and viral proteins. Other in vitro studies as well as in vivo experiments in rodents following mechanical stimulation, show that activated microglia and brain macrophages express high affinity glutamate transporters. These data have been confirmed in chronic inflammation of the brain, particularly in SIV infection, where activated microglia and brain macrophages also express glutamine synthetase. Recent studies in humans with HIV infection show that activated microglia and brain macrophages express the glutamate transporter EAAT-1 and that expression varies according to the disease stage. This suggests that, besides their recognized neurotoxic properties in HIV infection, these cells also have a neuroprotective function, and may partly make up for the inhibited astrocytic function, at least temporarily. This hypothesis might explain the discrepancy between microglial activation which occurs early in the disease, and neuronal apoptosis and neuronal loss which is a late event. In this review article, we discuss the possible neuroprotective and neurotrophic roles of activated microglia and macrophages that may be generated by the expression of high affinity glutamate transporters and glutamine synthetase, 2 major effectors of glial glutamate metabolism, and the implications for HIV-induced neuronal dysfunction, the underlying cause of HIV dementia.

The changing pattern of HIV neuropathology in the HAART era.

Highly active antiretroviral treatment (HAART), which has been available for most AIDS patients in France since 1996, has resulted in a dramatic improvement of the progression of the disease. From the survey of our series of 343 brains with acquired immunodeficiency syndrome (AIDS) from patients who died between 1985 and 2002, we found both quantitative and qualitative changes in the pattern of human immunodeficiency virus (HIV) neuropathology. Quantitatively, despite a dramatic decrease in the number of autopsies, brain involvement remained a major cause of death. There was an overall decrease in incidence of cerebral toxoplasmosis, cytomegalovirus encephalitis (CMVE), and HIV encephalitis (HIVE), for which successful treatment is available. This contrasted with the unchanged incidence of progressive multifocal leukoencephalopathy (PML) and malignant non-Hodgkin lymphomas (MNHL). However, when looking closer at the 3 last years, the incidence of diseases affecting patients with severe immunodepression (CMVE, PML, and MNHL) decreased between 2000 and 2002, whereas infections occurring in patients with milder immunodeficiency, toxoplasmosis, varicella-zoster encephalitis (VZVE), or herpes simplex virus encephalitis (HSVE) became more frequent. In addition, we found uncommon types of brain infection such as BK virus encephalitis or general paresis. Finally, we described new variants of HIVE: severe leukoencephalopathy with intense perivascular macrophage and lymphocyte infiltration, possibly due to an exaggerated response from a newly reconstituted immune system, and chronic "burnt out" forms of HIVE as VZVE, toxoplasmosis, or PML, possibly associated with prolonged survival, in which neither inflammation nor organisms could be detected. These findings are compared with those reported in other neuropathological studies from different developed countries.

Expression of excitatory amino acid transporter-1 in brain macrophages and microglia of HIV-infected patients. A neuroprotective role for activated microglia?

Recent experimental studies showed that activated macrophages/microglia (AMM) express excitatory amino acid transporters (EAATs), suggesting that, in addition to their neurotoxic properties, they also have a neuroprotective role by clearing extracellular glutamate and producing antioxidant glutathione. To test this hypothesis in human, the brain of 12 HIV-positive patients and 3 controls were immunostained for EAAT-1. EAAT-1 was expressed by AMM in all HIV-infected cases but not in HIV-negative controls. Expression varied according to the disease stage. In 5 cases with active HIV-encephalitis (HIVE), AMM strongly expressed EAAT-1 in the white matter and basal ganglia, analogous to HLA-DR and CD68 expression. There was weaker expression in the cortex and perineuronal microglial cells were not involved. In a case with "burnt out" HIVE following highly active antiretroviral therapy (HAART), EAAT-1 expression was mild, identical to that of HLA-DR and CD68 in the white matter and cortex and involved perineuronal microglial cells. In 3 AIDS patients without HIVE and in 3 pre-AIDS cases, EAAT-1 expression in the white matter was weaker than HLA-DR and CD68 expression; there was stronger correlation in the gray matter where perineuronal microglial cells were stained predominantly. Our findings in humans tend to confirm that AMM, particularly perineuronal microglial cells, play a neuroprotective role in the early stages of HIV infection and, possibly, following treatment. This is in keeping with the early microglial activation seen in pre-AIDS cases, and the late occurrence of neuronal loss. It may also explain the reversible cognitive disorders following treatment in some cases.

[The neuropathology of HIV infection in the era of highly active antiretroviral therapy]. / La pathologie du système nerveux central liée au VIH à l'ère des multithérapies.

Introduction of Highly Active Antiretroviral Treatment (HAART) which is available for most AIDS patients in France since 1996, has resulted in a dramatic improvement of the disease course. From the survey of our autopsy series of (AIDS) cases and the review of other neuropathological studies from different developed countries, we found quantitative and qualitative changes in the pattern of human immunodeficiency virus (HIV) neuropathology. Quantitatively, there was a dramatic decrease in the number of autopsy cases but brain involvement remained a major cause of death in AIDS patients. There was an overall decrease of cerebral toxoplasmosis, cytomegalovirus encephalitis (CMVE) and HIV encephalitis (HIVE) for which successful treatment is available. This contrasted with the unchanged incidence of progressive multifocal leucoencephalopathy (PML) and primary malignant non Hodgkin brain lymphomas (PMBL). However, when looking closer at the last three years, the incidence of diseases affecting patients with severe immunodepression (CMVE, PML, PMBL) decreased in 2000-2002, whereas infections occurring in patients with milder immunodeficiency (toxoplasmosis, varicella-zoster encephalitis (VZVE) or herpes simplex virus encephalitis (HSVE) became more frequent. Qualitatively, there were uncommon types of brain infections, such as BK virus encephalitis or general paresis. Finally, new forms of HIVE were reported: severe leukoencephalopathy with intense perivascular macrophage and lymphocyte infiltration possibly due to an exaggerated response from a newly reconstituted immune system; and also chronic "burnt out" forms of HIVE as VZVE, toxoplasmosis, or PML in which no inflammation and no infectious agent could be detected, likely due to prolonged survival.