The human microglia responsome: a resource for microglia states in health and disease.

Microglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are yet poorly understood.

Inflammatory markers in pregnancy - identifying drivers in four large cohorts.

Introduction: Adaptations of the immune system throughout gestation have been proposed as important mechanisms regulating successful pregnancy. Dysregulation of the maternal immune system has been associated with adverse maternal and fetal outcomes. The design and interpretation of human biomarker studies require additional insights in the trajectories and drivers of peripheral immune markers.

Maternal Immune Activation During Pregnancy and Obstetric Outcomes: A Population-Based Cohort Study.

Objective: Maternal immune activation has been proposed as a mechanism for adverse pregnancy outcomes, yet the mechanisms and effects of timing remain unclear. Immune disruption in early gestation may be particularly detrimental as this is an important period for placental development, which has been associated with the pathology of adverse obstetric outcomes. To increase our understanding of risk factors for adverse obstetric outcomes, we aim to investigate the association between multiple inflammatory and angiogenic markers during early pregnancy and adverse pregnancy outcomes in a large population-based cohort.

Microglia Exhibit a Unique Intact HIV Reservoir in Human Postmortem Brain Tissue.

A proviral reservoir persists within the central nervous system (CNS) of people with HIV, but its characteristics remain poorly understood. Research has primarily focused on cerebrospinal fluid (CSF), as acquiring brain tissue is challenging. We examined size, cellular tropism, and infection-dynamics of the viral reservoir in post-mortem brain tissue from five individuals on and off antiretroviral therapy (ART) across three brain regions.

General pathophysiology of neuroglia.

Neuroglia in the CNS, represented by astroglia, oligodendroglia, and microglia, are responsible for the homeostatic support and protection of the nervous tissue. Neuroglia are intimately involved in the pathogenesis of all neurologic diseases, and neuroglial changes to a large extent define the progression of these diseases and their neurologic outcome. In contrast to neurons, neuroglia are capable of mounting an evolutionary conserved response to pathology known as reactive gliosis.

Orchestrating the neuroglial compartment: Ontogeny and developmental interaction of astrocytes, oligodendrocytes, and microglia.

Neuroglial cells serve as the master regulators of the central nervous system, making it imperative for glial development to be tightly regulated both spatially and temporally to ensure optimal brain function. In this chapter, we will discuss the origin and development of the three major glia cells such as astrocytes, oligodendrocytes, and microglia in the central nervous system. While much of our understanding of neuroglia development stems from studies using animal models, we will also explore recent insights into human glial development and potential differences from rodent models.

Neuroglia in the healthy brain.

The nervous tissue is composed of neurons and neuroglia, which by working in a tightly coordinated manner, define the function of the nervous system. Neuroglia, defined as homeostatic and defensive cells of the nervous system, are highly heterogeneous in form and function and are endowed with a remarkable plasticity that allows life-long adaptation to environmental challenges. Neuroglia of the peripheral nervous system are represented by myelinating, nonmyelinating, perisynaptic, and cutaneous Schwann cells, satellite glia of sensory and sympathetic ganglia and enteric glia of the enteric nervous system.

Long-read RNA sequencing atlas of human microglia isoforms elucidates disease-associated genetic regulation of splicing.

Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. Mapping the genetics of gene expression in human microglia has identified several loci associated with disease-associated genetic variants in microglia-specific regulatory elements. However, identifying genetic effects on splicing is challenging because of the use of short sequencing reads.

A microglia-containing cerebral organoid model to study early life immune challenges.

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs.

Clinical symptoms and psychosocial functioning in patients with schizophrenia spectrum disorders testing seropositive for anti-NMDAR antibodies: a case-control comparison with patients testing negative.

Background: Antibodies against the N-methyl-D-aspartate receptor (NMDAR) have been described in the serum of people with schizophrenia spectrum disorders (schizophrenia). However, the prevalence and clinical relevance of these antibodies in schizophrenia is unclear. This knowledge gap includes the possibility of such antibodies being associated with a distinct clinical profile, which in turn might warrant a distinct treatment approach.

Emerging Models to Study Human Microglia In vitro.

New in vitro models provide an exciting opportunity to study live human microglia. Previously, a major limitation in understanding human microglia in health and disease has been their limited availability. Here, we provide an overview of methods to obtain human stem cell or blood monocyte-derived microglia-like cells that provide a nearly unlimited source of live human microglia for research.

Inflammatory markers in pregnancy - surprisingly stable. Mapping trajectories and drivers in four large cohorts.

Adaptations of the immune system throughout gestation have been proposed as important mechanisms regulating successful pregnancy. Dysregulation of the maternal immune system has been associated with adverse maternal and fetal outcomes. To translate findings from mechanistic preclinical studies to human pregnancies, studies of serum immune markers are the mainstay.

A microglia-containing cerebral organoid model to study early life immune challenges.

Prenatal infections and activation of the maternal immune system have been proposed to contribute to causing neurodevelopmental disorders (NDDs), chronic conditions often linked to brain abnormalities. Microglia are the resident immune cells of the brain and play a key role in neurodevelopment. Disruption of microglial functions can lead to brain abnormalities and increase the risk of developing NDDs.

The effect of SARS-CoV-2 infection and vaccination on Th17 and regulatory T cells in a pregnancy cohort in NYC.

Disturbances in T-cells, specifically the Th17/Treg balance, have been implicated in adverse pregnancy outcomes. We investigated these two T-cell populations following pre-pregnancy and pregnancy SARS-CoV-2 infection and COVID-19 vaccination in 351 participants from a pregnancy cohort in New York City (Generation C; 2020-2022). SARS-CoV-2 infection status was determined via laboratory or medical diagnosis and COVID-19 vaccination status via survey and electronic medical records data.

Exploring peripheral biomarkers of response to simvastatin supplementation in schizophrenia.

Schizophrenia is one of the most debilitating mental disorders, and its diagnosis and treatment present significant challenges. Several clinical trials have previously evaluated the effectiveness of simvastatin, a lipid-lowering medication, as a novel add-on treatment for schizophrenia. However, treatment effects varied highly between patients and over time.

Association between doxycycline use and long-term functioning in patients with schizophrenia.

Importance And Objective: The brain-penetrant tetracycline antibiotics, minocycline and doxycycline, have been proposed as potential candidate drugs for treatment of schizophrenia, based on preclinical studies and clinical trials. A potential long-term beneficial effect of these antibiotics for schizophrenia patients has not been investigated. This study was designed to determine if redemption of doxycycline prescription in schizophrenia is associated with decreased incidence of disability pension, a proxy for long-term functioning.

Increased postpartum anxiety symptoms after perinatal SARS-CoV-2 infection in a large, prospective pregnancy cohort in New York City.

Numerous studies reported an increase of postpartum mood symptoms during the COVID-19 pandemic. Yet, the link between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and perinatal mental health is less well understood. We investigated the associations between prenatal SARS-CoV-2 infection and postpartum depressive and anxiety symptoms, including examinations of infection timing and pandemic timeline.

Long-read RNA-seq atlas of novel microglia isoforms elucidates disease-associated genetic regulation of splicing.

Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. We previously mapped the genetic regulation of gene expression and mRNA splicing in human microglia, identifying several loci where common genetic variants in microglia-specific regulatory elements explain disease risk loci identified by GWAS. However, identifying genetic effects on splicing has been challenging due to the use of short sequencing reads to identify causal isoforms.

The human microglia responsome: a resource to better understand microglia states in health and disease.

Unlabelled: Microglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are as yet poorly understood.

Transcriptomic and morphological maturation of human astrocytes in cerebral organoids.

Cerebral organoids (CerOrgs) derived from human induced pluripotent stem cells (iPSCs) are a valuable tool to study human astrocytes and their interaction with neurons and microglia. The timeline of astrocyte development and maturation in this model is currently unknown and this limits the value and applicability of the model. Therefore, we generated CerOrgs from three healthy individuals and assessed astrocyte maturation after 5, 11, 19, and 37 weeks in culture.

Gene expression profiling of monocytes in recent-onset schizophrenia.

Immune-related mechanisms have been suggested to be involved in schizophrenia. Various studies have shown changes in monocytes isolated from the blood of schizophrenia patients, including changes in monocyte numbers, as well as altered protein and transcript levels of important markers. However, validation of these findings and understanding how these results are related to immune-related changes in the brain and schizophrenia genetic risk factors, is limited.

A Sex-Dependent Association Between Doxycycline Use and Development of Schizophrenia.

Background: Doxycycline and minocycline are brain-penetrant tetracycline antibiotics, which recently gained interest because of their immunomodulatory and neuroprotective properties. Observational studies have suggested that exposure to these drugs may decrease the risk to develop schizophrenia, but results are inconsistent. The aim of this study was to investigate the potential association between doxycycline use and later onset of schizophrenia.

Microglia-mediated synaptic pruning as a key deficit in neurodevelopmental disorders: Hype or hope?

There is a consensus in the field that microglia play a prominent role in neurodevelopmental processes like synaptic pruning and neuronal network maturation. Thus, a current momentum of associating microglia deficits with neurodevelopmental disorders (NDDs) emerged. This concept is challenged by rodent studies and clinical data.