Inhibition of lipid synthesis by the HIV integrase strand transfer inhibitor elvitegravir in primary rat oligodendrocyte cultures.

Combined antiretroviral therapy (cART) has greatly decreased mortality and morbidity among persons with HIV; however, neurologic impairments remain prevalent, in particular HIV-associated neurocognitive disorders (HANDs). White matter damage persists in cART-treated persons with HIV and may contribute to neurocognitive dysfunction as the lipid-rich myelin membrane of oligodendrocytes is essential for efficient nerve conduction. Because of the importance of lipids to proper myelination, we examined the regulation of lipid synthesis in oligodendrocyte cultures exposed to the integrase strand transfer inhibitor elvitegravir (EVG), which is administered to persons with HIV as part of their initial regimen.

White matter injury across neurodegenerative disease.

Oligodendrocytes (OLs), the myelin-generating cells of the central nervous system (CNS), are active players in shaping neuronal circuitry and function. It has become increasingly apparent that injury to cells within the OL lineage plays a central role in neurodegeneration. In this review, we focus primarily on three degenerative disorders in which white matter loss is well documented: Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS).

Antiretroviral treatment reveals a novel role for lysosomes in oligodendrocyte maturation.

White matter deficits are a common neuropathologic finding in neurologic disorders, including HIV-associated neurocognitive disorders (HAND). In HAND, the persistence of white matter alterations despite suppressive antiretroviral (ARV) therapy suggests that ARVs may be directly contributing to these impairments. Here, we report that a frontline ARV, bictegravir (BIC), significantly attenuates remyelination following cuprizone-mediated demyelination, a model that recapitulates acute demyelination, but has no impact on already formed mature myelin.

Motor Learning and Physical Exercise in Adaptive Myelination and Remyelination.

The idea that myelination is driven by both intrinsic and extrinsic cues has gained much traction in recent years. Studies have demonstrated that myelination occurs in an intrinsic manner during early development and continues through adulthood in an activity-dependent manner called adaptive myelination. Motor learning, the gradual acquisition of a specific novel motor skill, promotes adaptive myelination in both the healthy and demyelinated central nervous system (CNS).

Further Delineation of the Clinical and Pathologic Features of HIKESHI-Related Hypomyelinating Leukodystrophy.

Background: A recurrent homozygous missense variant, c.160G>C;p.(Val54Leu) in HIKESHI, was found to cause a hypomyelinating leukodystrophy with high frequency in the Ashkenazi Jewish population.

HIV-induced neuroinflammation inhibits oligodendrocyte maturation via glutamate-dependent activation of the PERK arm of the integrated stress response.

Despite combined antiretroviral therapy (cART), HIV-associated neurocognitive disorder (HAND) affects 30-50% of HIV-positive patients. Importantly, persistent white matter pathologies, specifically corpus callosum thinning and disruption of white matter microstructures observed in patients with HAND despite viral control through cART, raise the possibility that HIV infection in the setting of suboptimal cART may perturb oligodendrocyte (OL) maturation, function and/or survival, influencing HAND persistence in the cART era. To examine the effect of HIV infection on OL maturation, we used supernatants of primary human monocyte-derived macrophages infected with HIV (HIV/MDMs) to treat primary cultures of rat oligodendrocyte precursor cells (OPCs) during their differentiation to mature OLs.

Inducible knockout of Clec16a in mice results in sensory neurodegeneration.

CLEC16A has been shown to play a role in autophagy/mitophagy processes. Additionally, genetic variants in CLEC16A have been implicated in multiple autoimmune diseases. We generated an inducible whole-body knockout, Clec16a mice, to investigate the loss of function of CLEC16A.

The Wnt Effector TCF7l2 Promotes Oligodendroglial Differentiation by Repressing Autocrine BMP4-Mediated Signaling.

Promoting oligodendrocyte (OL) differentiation represents a promising option for remyelination therapy for treating the demyelinating disease multiple sclerosis (MS). The Wnt effector transcription factor 7-like 2 (TCF7l2) was upregulated in MS lesions and had been proposed to inhibit OL differentiation. Recent data suggest the opposite yet underlying mechanisms remain elusive.

Differential effects of integrase strand transfer inhibitors, elvitegravir and raltegravir, on oligodendrocyte maturation: A role for the integrated stress response.

Regardless of adherence to combined antiretroviral therapy, white matter and myelin pathologies persist in patients with HIV-associated neurocognitive disorders, a spectrum of cognitive, motor, and behavioral impairments. We hypothesized that antiretroviral therapy alters the maturation of oligodendrocytes which synthesize myelin. We tested whether specific frontline integrase strand transfer inhibitors would alter oligodendrocyte differentiation and myelination.

Inhibitors of Myelination and Remyelination, Bone Morphogenetic Proteins, are Upregulated in Human Neurological Disease.

During demyelinating disease such as multiple sclerosis and stroke, myelin is destroyed and along with it, the oligodendrocytes that synthesize the myelin. Thus, recovery is limited due to both interruptions in neuronal transmission as well as lack of support for neurons. Although oligodendrocyte progenitor cells remain abundant in the central nervous system, they rarely mature and form new functional myelin in the diseased CNS.

Reducing Th2 inflammation through neutralizing IL-4 antibody rescues myelination in IUGR rat brain.

Background: Intrauterine growth restriction (IUGR) is a common complication of pregnancy and is associated with significant neurological deficits in infants, including white matter damage. Previous work using an animal model of IUGR has demonstrated that IUGR rats exhibit neurobehavioral deficits and developmental delays in oligodendrocyte maturation and myelination, but the mechanisms which cause this delay are unknown. Inflammation may be an important etiological factor in IUGR and has been recognized as playing a fundamental role in the pathogenesis of myelin disorders, including cerebral palsy.

Protease Inhibitors, Saquinavir and Darunavir, Inhibit Oligodendrocyte Maturation: Implications for Lysosomal Stress.

Despite the introduction of antiretroviral (ARV) therapy (ART), approximately 30-50% of people living with human immunodeficiency virus-1 (HIV-1) will develop a spectrum of measurable neurocognitive dysfunction, collectively called HIV-associated neurocognitive disorder (HAND). While the clinical manifestations of HAND have changed with the advent of ART, certain pathological features have endured, including white matter alterations and dysfunction. The persistence of white matter alterations in the post-ART era suggests that ARV drugs themselves may contribute to HAND pathology.

Prenatal hypoxemia alters microglial morphology in fetal sheep.

Objective: Neuroimmune cells, particularly microglia and astrocytes, play a critical role in neurodevelopment. Neurocognitive delays are common in children with congenital heart disease, but their etiology is poorly understood. Our objective was to determine whether prenatal hypoxemia, at levels common in congenital heart disease, induced neuroimmune activation to better understand the origins of neurobehavioral disorders in congenital heart disease.

Ex Utero Extracorporeal Support as a Model for Fetal Hypoxia and Brain Dysmaturity.

Background: Congenital heart disease (CHD) is associated with abnormal fetal brain development, a phenomenon that may be related to decreased cerebral oxygen delivery in utero. We used an artificial womb model to test the hypothesis that decreasing fetal oxygen delivery would reproduce physiologic changes identified in fetuses with CHD.

Methods: Experimental (hypoxemic) fetal lambs (mean gestational age, 111 ± 3 days; n = 4) and control animals (112 days; n = 5) were maintained in the artificial womb for a mean of 22 ± 6 days.

White matter loss and oligodendrocyte dysfunction in HIV: A consequence of the infection, the antiretroviral therapy or both?

While the severe cognitive effects of HIV-associated dementia have been reduced by combined antiretroviral therapy (cART), nearly half of HIV-positive (HIV+) patients still suffer from some form of HIV-Associated Neurocognitive Disorders (HAND). While frank neuronal loss has been dramatically reduced in HAND patients, white matter loss, including dramatic thinning of the corpus callosum, and loss of volume and structural integrity of myelin persists despite viral control by cART. It remains unclear whether changes in white matter underlie the clinical manifestation seen in patients or whether they are the result of persistent viral reservoirs, remnant damage from the acute infection, the antiretroviral compounds used to treat HIV, secondary effects due to peripheral toxicities or other associated comorbid conditions.

Chronic intrauterine hypoxia alters neurodevelopment in fetal sheep.

Objective: We tested the hypothesis that chronic fetal hypoxia, at a severity present in many types of congenital heart disease, would lead to abnormal neurodevelopment.

Methods: Eight mid-gestation fetal sheep were cannulated onto a pumpless extracorporeal oxygenator via the umbilical vessels and supported in a fluid-filled environment for 22 ± 2 days under normoxic or hypoxic conditions. Total parenteral nutrition was provided.

Arx Expression Suppresses Ventralization of the Developing Dorsal Forebrain.

Early brain development requires a tight orchestration between neural tube patterning and growth. How pattern formation and brain growth are coordinated is incompletely understood. Previously we showed that aristaless-related homeobox (ARX), a paired-like transcription factor, regulates cortical progenitor pool expansion by repressing an inhibitor of cell cycle progression.

Reduced sterol regulatory element-binding protein (SREBP) processing through site-1 protease (S1P) inhibition alters oligodendrocyte differentiation in vitro.

The formation of the myelin membrane of the oligodendrocyte in the CNS is a fundamental process requiring the coordinated synthesis of many different components. The myelin membrane is particularly rich in lipids, however, the regulation of this lipid synthesis is not understood. In other cell types, including Schwann cells, the myelin-forming cells of the PNS, lipid synthesis is tightly regulated by the sterol regulatory element-binding protein (SREBP) family of transcription factors, but this has not been previously shown in oligodendrocytes.

Gliopathy of Demyelinating and Non-Demyelinating Strains of Mouse Hepatitis Virus.

Demyelination in the central nervous system induced by neurovirulent strains of Mouse Hepatitis Virus (MHV) is mediated by the viral spike glycoprotein, but it is not clear whether the mechanism of this disease pathology involves direct viral infection of oligodendrocytes. Detailed studies of glial cell tropism of MHV are presented, demonstrating that direct MHV infection of oligodendrocytes differs between demyelinating (RSA59) and non-demyelinating (RSMHV2) viral strains both in vitro and in vivo. Our results indicate that direct injury of mature oligodendrocytes is an important mechanism of virus-induced demyelination.

Altered Oligodendrocyte Maturation and Myelin Maintenance: The Role of Antiretrovirals in HIV-Associated Neurocognitive Disorders.

Despite effective viral suppression through combined antiretroviral therapy (cART), approximately half of HIV-positive individuals have HIV-associated neurocognitive disorders (HAND). Studies of antiretroviral-treated patients have revealed persistent white matter abnormalities including diffuse myelin pallor, diminished white matter tracts, and decreased myelin protein mRNAs. Loss of myelin can contribute to neurocognitive dysfunction because the myelin membrane generated by oligodendrocytes is essential for rapid signal transduction and axonal maintenance.

Bone Morphogenetic Proteins: Inhibitors of Myelination in Development and Disease.

Myelin, the lipid membrane that surrounds axons, is critical for the propagation of nervous impulses and axonal maintenance. The destruction of myelin or lack of myelin formation due to disease or injury causes severe motor and cognitive disability. Regeneration of myelin is theoretically possible but rarely happens.

Long-term intermittent hypoxia elevates cobalt levels in the brain and injures white matter in adult mice.

Study Objectives: Exposure to the variable oxygenation patterns in obstructive sleep apnea (OSA) causes oxidative stress within the brain. We hypothesized that this stress is associated with increased levels of redox-active metals and white matter injury.

Design: Participants were randomly allocated to a control or experimental group (single independent variable).

Cell-type-specific activation of the oligoadenylate synthetase-RNase L pathway by a murine coronavirus.

Previous studies have demonstrated that the murine coronavirus mouse hepatitis virus (MHV) nonstructural protein 2 (ns2) is a 2',5'-phosphodiesterase that inhibits activation of the interferon-induced oligoadenylate synthetase (OAS)-RNase L pathway. Enzymatically active ns2 is required for efficient MHV replication in macrophages, as well as for the induction of hepatitis in C57BL/6 mice. In contrast, following intranasal or intracranial inoculation, efficient replication of MHV in the brain is not dependent on an enzymatically active ns2.

Delayed myelination in an intrauterine growth retardation model is mediated by oxidative stress upregulating bone morphogenetic protein 4.

Intrauterine growth retardation (IUGR) is associated with neurological deficits including cerebral palsy and cognitive and behavioral disabilities. The pathogenesis involves oxidative stress that leads to periventricular white matter injury with a paucity of mature oligodendrocytes and hypomyelination. The molecular mechanisms underlying this damage remain poorly understood.