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A Thin-skull Window Technique for Chronic Two-photon In vivo Imaging of Murine Microglia in Models of Neuroinflammation
Published on: September 20, 2010
Microglia in human immunodeficiency virus-associated neurodegeneration
1Department of Neurology, University of Washington, Seattle, Washington.
Abstract:
Infection with the human immunodeficiency virus (HIV) is associated with a syndrome of cognitive and motor abnormalities that may develop in the absence of opportunistic infections. Neurons are not productively infected by HIV. Thus, one hypothesis to explain the pathophysiology of HIV-associated dementia (HAD) suggests that signals released from other infected cell types in the CNS secondarily lead to neuronal injury. Microglia are the predominant resident CNS cell type productively infected by HIV-1. Neurologic dysfunction in HAD appears to be a consequence of microglial infection and activation. Several neurotoxic immunomodulatory factors are released from infected and activated microglia, leading to altered neuronal function, synaptic and dendritic degeneration, and eventual neuronal apoptosis. This review summarizes findings from clinical/pathological studies, animal models, and in vitro models of HAD. Most of these studies support the hypothesis that altered microglial physiology is the nidus for a cascade of events leading to neuronal dysfunction and death. Several molecular mediators of neuronal injury in HAD that emanate from microglia have been identified, and strategies for altering the impact of these neurotoxins are discussed.
Insights
Human immunodeficiency virus (HIV) infection can cause HIV-associated dementia (HAD) without opportunistic infections. Activated microglia release neurotoxins, causing neuronal injury and cognitive decline.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Human immunodeficiency virus (HIV) infection is linked to neurological disorders, including HIV-associated dementia (HAD).
- Neurons are not directly infected by HIV, suggesting indirect mechanisms for neurodegeneration.
- Microglia, the primary HIV-infected cells in the central nervous system (CNS), are implicated in HAD pathogenesis.
Purpose of the Study:
- To review the pathophysiology of HIV-associated dementia (HAD).
- To explore the role of microglia in HIV-induced neurotoxicity.
- To identify molecular mediators of neuronal injury and potential therapeutic strategies.
Main Methods:
- Review of clinical and pathological studies.
- Analysis of animal models of HAD.
- Examination of in vitro models of microglial activation and neurotoxicity.
Main Results:
- Microglial infection and activation are central to neurological dysfunction in HAD.
- Activated microglia release neurotoxic factors that damage neurons and synapses.
- Evidence supports microglial dysfunction as the initiating event in a cascade of neuronal injury.
Conclusions:
- Altered microglial function drives neuronal damage in HAD.
- Identification of microglial-derived neurotoxins offers therapeutic targets.
- Interventions aimed at modulating microglial activity may mitigate HAD progression.
