Accelerated neurodegeneration of basal forebrain cholinergic neurons in HIV-1 gp120 transgenic mice: Critical role of the p75 neurotrophin receptor.

Human Immunodeficiency Virus-1 (HIV) infection of the brain induces HIV-associated neurocognitive disorders (HAND). The set of molecular events employed by HIV to drive cognitive impairments in people living with HIV are diverse and remain not completely understood. We have shown that the HIV envelope protein gp120 promotes loss of synapses and decreases performance on cognitive tasks through the p75 neurotrophin receptor (p75).

Mice deficient for G-protein-coupled receptor 75 display altered presynaptic structural protein expression and disrupted fear conditioning recall.

There are a number of G-protein-coupled receptors (GPCRs) that are considered "orphan receptors" because the information on their known ligands is incomplete. Yet, these receptors are important targets to characterize, as the discovery of their ligands may lead to potential new therapies. GPR75 was recently deorphanized because at least two ligands appear to bind to it, the chemokine CCL5 and the eicosanoid 20-Hydroxyeicosatetraenoic acid.

Recent Advances in the Molecular and Cellular Mechanisms of gp120-Mediated Neurotoxicity.

Axonal degeneration and loss of synapses are often seen in different brain areas of people living with human immunodeficiency virus (HIV). Nevertheless, the underlying causes of the pathological alterations observed in these individuals are poorly comprehended, considering that HIV does not infect neurons. Experimental data have shown that viral proteins, including the envelope protein gp120, cause synaptic pathology followed by neuronal cell death.

Extracellular Vesicles and HIV-Associated Neurocognitive Disorders: Implications in Neuropathogenesis and Disease Diagnosis.

Extracellular vesicles are heterogeneous cell-derived membranous structures of nanometer size that carry diverse cargoes including nucleic acids, proteins, and lipids. Their secretion into the extracellular space and delivery of their cargo to recipient cells can alter cellular function and intracellular communication. In this review, we summarize the role of extracellular vesicles in the disease pathogenesis of HIV-associated neurocognitive disorder (HAND) by focusing on their role in viral entry, neuroinflammation, and neuronal degeneration.

Race-Dependent Association of Single-Nucleotide Polymorphisms in TrkB Receptor in People Living with HIV and Depression.

Human immunodeficiency virus (HIV)-associated cognitive disorders (HAND) is characterized by impaired motor and intellectual functions, as well as mood disorders. Brain-derived neurotrophic factor and its receptor TrkB (or NTRK2) mediate the efficacy of antidepressant drugs. Genomic studies of BDNF/TrkB have implicated common single-nucleotide polymorphisms in the pathology of depression.

Neuronal apoptosis induced by morphine withdrawal is mediated by the p75 neurotrophin receptor.

Morphine withdrawal evokes neuronal apoptosis through mechanisms that are still under investigation. We have previously shown that morphine withdrawal increases the levels of pro-brain-derived neurotrophic factor (BDNF), a proneurotrophin that promotes neuronal apoptosis through the binding and activation of the pan-neurotrophin receptor p75 (p75NTR). In this work, we sought to examine whether morphine withdrawal increases p75NTR-driven signaling events.

Up-regulation of the p75 neurotrophin receptor is an essential mechanism for HIV-gp120 mediated synaptic loss in the striatum.

Reduced synaptodendritic complexity appears to be a key feature in human immunodeficiency virus (HIV)-associated neurological disorder (HAND). Viral proteins, and in particular the envelope protein gp120, play a role in the pathology of synapses. Gp120 has been shown to increase both in vitro and in vivo the proneurotrophin brain-derived neurotrophic factor, which promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR).

HIV influences microtubule associated protein-2: potential marker of HIV-associated neurocognitive disorders.

Objective: Postmortem brains of patients diagnosed with HIV-1-associated neurocognitive disorders (HAND) exhibit loss of dendrites. However, the mechanisms by which synapses are damaged are not fully understood.

Design: Dendrite length and remodeling occurs via microtubules, the dynamics of which are regulated by microtubule-binding proteins, including microtubule-associated protein 2 (MAP2).

Increased matrix metalloproteinase levels and perineuronal net proteolysis in the HIV-infected brain; relevance to altered neuronal population dynamics.

HIV-associated neurocognitive disorders (HAND) continue to persist despite effective control of viral replication. Although the mechanisms underlying HAND are poorly understood, recent attention has focused on altered neuronal population activity as a correlate of impaired cognition. However, while alterations in neuronal population activity in the gamma frequency range are noted in the setting of HAND, the underlying mechanisms for these changes is unclear.

Reversal of Cognitive Impairment in gp120 Transgenic Mice by the Removal of the p75 Neurotrophin Receptor.

Activation of the p75 neurotrophin receptor (p75NTR), by the proneurotrophin brain-derived neurotrophic factor (proBDNF), triggers loss of synapses and promotes neuronal death. These pathological features are also caused by the human immunodeficiency virus-1 (HIV) envelope protein gp120, which increases the levels of proBDNF. To establish whether p75NTR plays a role in gp120-mediated neurite pruning, we exposed primary cultures of cortical neurons from mice to gp120.

Histone deacetylase 6 inhibition rescues axonal transport impairments and prevents the neurotoxicity of HIV-1 envelope protein gp120.

Despite successful antiretroviral drug therapy, a subset of human immunodeficiency virus-1 (HIV)-positive individuals still display synaptodendritic simplifications and functional cognitive impairments referred to as HIV-associated neurocognitive disorders (HANDs). The neurological damage observed in HAND subjects can be experimentally reproduced by the HIV envelope protein gp120. However, the complete mechanism of gp120-mediated neurotoxicity is not entirely understood.

Age-Related Decrease in Tyrosine Hydroxylase Immunoreactivity in the Substantia Nigra and Region-Specific Changes in Microglia Morphology in HIV-1 Tg Rats.

Animal models have been used to study cellular processes related to human immunodeficiency virus-1 (HIV-1)-associated neurocognitive disorders (HAND). The HIV-1 transgenic (Tg) rat expresses HIV viral genes except the gag-pol replication genes and exhibits neuropathological features similar to HIV patients receiving combined antiretroviral therapy (cART). Using this rat, alterations in dopaminergic function have been demonstrated; however, the data for neuroinflammation and glial reactivity is conflicting.

Helix-A peptide prevents gp120-mediated neuronal loss.

Aim: The human-immunodeficiency virus (HIV) envelope protein gp120 promotes synaptic damage similar to that observed in people living with HIV who have neurocognitive disorders. The neurotoxic effect of gp120 appears to occur through the α-helix motif that binds to neuronal microtubules (MTs). In this study, we examined the ability of short peptide derivatives from Helix-A, a peptide synthesized based on α-helix structure of gp120, to displace gp120 from binding to MTs and prevent its neurotoxic effects.

HIV-1 Tat promotes astrocytic release of CCL2 through MMP/PAR-1 signaling.

The HIV-1 protein Tat is continually released by HIV-infected cells despite effective combination antiretroviral therapies (cART). Tat promotes neurotoxicity through enhanced expression of proinflammatory molecules from resident and infiltrating immune cells. These molecules include matrix metalloproteinases (MMPs), which are pathologically elevated in HIV, and are known to drive central nervous system (CNS) injury in varied disease settings.

HIV-associated neurodegeneration: exploitation of the neuronal cytoskeleton.

Human immunodeficiency virus-1 (HIV) infection of the central nervous system damages synapses and promotes axonal injury, ultimately resulting in HIV-associated neurocognitive disorders (HAND). The mechanisms through which HIV causes damage to neurons are still under investigation. The cytoskeleton and associated proteins are fundamental for axonal and dendritic integrity.

The orphan G-protein-coupled receptor 75 signaling is activated by the chemokine CCL5.

The chemokine CCL5 prevents neuronal cell death mediated both by amyloid β, as well as the human immunodeficiency virus viral proteins gp120 and Tat. Because CCL5 binds to CCR5, CCR3 and/or CCR1 receptors, it remains unclear which of these receptors plays a role in neuroprotection. Indeed, CCL5 also has neuroprotective activity in cells lacking these receptors.

Human immunodeficiency virus Tat impairs mitochondrial fission in neurons.

Human immunodeficiency virus-1 (HIV) infection of the central nervous system promotes neuronal injury that culminates in HIV-associated neurocognitive disorders. Viral proteins, including transactivator of transcription (Tat), have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. Tat transgenic mice or neurons exposed to Tat, which show neuronal loss, exhibit smaller mitochondria as compared to controls.

Glial- and Neuronal-Specific Expression of CCL5 mRNA in the Rat Brain.

Chemokine (C-C motif) ligand 5 (CCL5) belongs to a group of chemokines that play a role in the peripheral immune system, mostly as chemoattractant molecules, and mediate tactile allodynia. In the central nervous system (CNS), CCL5 and its receptors have multiple functions, including promoting neuroinflammation, insulin signaling, neuromodulator of synaptic activity and neuroprotection against a variety of neurotoxins. Evidence has also suggested that this chemokine may regulate opioid response.

Combination of Fluorescent Hybridization (FISH) and Immunofluorescence Imaging for Detection of Cytokine Expression in Microglia/Macrophage Cells.

Microglia and macrophage cells are the primary producers of cytokines in response to neuroinflammatory processes. But these cytokines are also produced by other glial cells, endothelial cells, and neurons. It is essential to identify the cells that produce these cytokines to target their different levels of activation.

Morphine Withdrawal Increases Brain-Derived Neurotrophic Factor Precursor.

Morphine has been shown to increase the expression of brain-derived neurotrophic factor (BDNF) in the brain. However, little is known about the effect of morphine withdrawal on BDNF and its precursor protein, or proBDNF, which induces neuronal apoptosis. In this work, we examined whether BDNF and proBDNF levels change in rats chronically injected with escalating doses of morphine and those who undergo spontaneous withdrawal for 60 h.

Human Immunodeficiency Virus Promotes Mitochondrial Toxicity.

Combined antiretroviral therapies (cART) have had remarkable success in reducing morbidity and mortality among patients infected with human immunodeficiency virus (HIV). However, mild forms of HIV-associated neurocognitive disorders (HAND), characterized by loss of synapses, remain. cART may maintain an undetectable HIV RNA load but does not eliminate the expression of viral proteins such as trans-activator of transcription (Tat) and the envelope glycoprotein gp120 in the brain.

Endocytic Trafficking of HIV gp120 is Mediated by Dynamin and Plays a Role in gp120 Neurotoxicity.

Neurons that endocytose the human immunodeficiency virus-1 (HIV) protein gp120 exhibit neurite retraction and activation of caspase-3, suggesting that the endocytic process may be crucial for gp120-mediated neuronal injury. The goal of this study is to demonstrate that internalization and accumulation of gp120 play a role in its neurotoxic effects. In mammalian cells, endocytosis is primarily a dynamin-dependent process.

The viral protein gp120 decreases the acetylation of neuronal tubulin: potential mechanism of neurotoxicity.

The human immunodeficiency virus (HIV) envelope protein gp120 promotes axonal damage and neurite pruning, similar to that observed in HIV-positive subjects with neurocognitive disorders. Thus, gp120 has been used to examine molecular and cellular pathways underlying HIV-mediated neuronal dysfunction. Gp120 binds to tubulin beta III, a component of neuronal microtubules.

The neurotrophin receptor p75 mediates gp120-induced loss of synaptic spines in aging mice.

Human immunodeficiency virus 1 and its envelope protein gp120 reduce synaptodendritic complexity. However, the mechanisms contributing to this pathological feature are still not understood. The proneurotrophin brain-derived neurotrophic factor promotes synaptic simplification through the activation of the p75 neurotrophin receptor (p75NTR).