Neurotoxic reactive astrocytes are induced by activated microglia :

"Reactive astrocytes are strongly induced by central nervous system (CNS) injury and disease, but their role is poorly understood. Here we show that a subtype of reactive astrocytes, which we termed A1, is induced by classically activated neuroinflammatory microglia. We show that activated microglia induce A1 astrocytes by secreting Il-1α, TNF and C1q, and that these cytokines together are necessary and sufficient to induce A1 astrocytes. A1 astrocytes lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis, and induce the death of neurons and oligodendrocytes. Death of axotomized CNS neurons in vivo is prevented when the formation of A1 astrocytes is blocked. Finally, we show that A1 astrocytes are abundant in various human neurodegenerative diseases including Alzheimer’s, Huntington’s and Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. Taken together these findings help to explain why CNS neurons die after axotomy, strongly suggest that A1 astrocytes contribute to the death of neurons and oligodendrocytes in neurodegenerative disorders, and provide opportunities for the development of new treatments for these diseases."



'via Blog this'

Disrupted immunity in the fetal brain is linked to neurodevelopmental disorders

Disrupted fetal immune system development, such as that caused by viral infection in the mother, may be a key factor in the later appearance of certain neurodevelopmental disorders. This finding emerges from a Weizmann Institute study published in Science on June 23, 2016.
The study may explain, among other things, how the mother's infection with the cytomegalovirus (CMV) during pregnancy, which affects her own and her fetus's immune system, increases the risk that her offspring will develop autism or schizophrenia, sometimes years later. This increased risk of neurodevelopmental diseases had been discovered many years ago in epidemiological studies and confirmed in mouse models. The Weizmann study, led by Dr. Ido Amit and Prof. Michal Schwartz, of the Immunology and Neurobiology Departments, respectively, provides a possible explanation for this increase on the cellular and the mechanistic molecular levels.

Immune microglia clue to preventing schizophrenia - BBC News

It may be possible to prevent schizophrenia by calming the brain's immune system, say scientists.
Brain scans found an overactive immune system in patients as well as in those at high risk of schizophrenia.The UK Medical Research Council team wants to test anti-inflammatory drugs to treat or even prevent the disease.The researchers analysed microglia, which are the cells that protect the brain from infection and also "prune" unwanted connections between brain cells.

The highest level was found in patients with the condition, but those deemed at high risk of developing schizophrenia also showed heightened activity levels.

Iron-containing inflammatory cells seen in Alzheimer's brains -- ScienceDaily

Examining post-mortem tissue from the brains of people with Alzheimer's disease, Stanford University School of Medicine investigators identified what appear to be iron-containing microglia -- specialized scavenger cells that sometimes become inflammatory -- in a particular part of the hippocampus, a key brain structure whose integrity is critical to memory formation.
The bulk of microglia found in association with iron in the study were in an activated, inflammatory state. Alzheimer's is increasingly understood to involve brain inflammation, and groups led by Stanford researchers such as neurologists Katrin Andreasson, MD, and Tony Wyss-Coray, PhD, and neurobiologist Ben Barres, MD, PhD, have previously fingered microglia as potential suspects in the early inflammatory pathology of the disease. This study adds the new finding that inflamed, iron-associated microglia are present in the hippocampus in Alzheimer's and are observable by 7T MRI, which could advance the scientific community's understanding of the disease.

Related articles AlzForum  Alzheimer’s Disease Linked to Superficial Siderosis (Cortical superficial siderosis (SS) is characterized by deposits of hemosiderin, an iron-containing breakdown product of blood, that line the outermost surface of the cortex )

• Final stage of normal inflammatory process may be disrupted in patients with Alzheimer's disease

Study links brain inflammation triggered by chronic pain to anxiety and depression -- ScienceDaily

In work with rodents, Catherine Cahill, associate professor of
anesthesiology & perioperative care at UCI, Christopher Evans of
UCLA's Brain Research Institute, and colleagues discovered that
pain-derived brain inflammation causes the accelerated growth and
activation of immune cells called microglia. These cells trigger
chemical signals within neurons that restrict the release of dopamine, a
neurotransmitter that helps control the brain's reward and pleasure
centers.

Systemic Inflammation: A Driver of Neurodegenerative Disease? | ALZFORUM

 Under healthy conditions, microglia look placid. They sit evenly spaced throughout the brain, processes extended, quietly doing their job of scanning for debris. When disease kicks in, these calm cells can transmogrify and end up doing more harm than good. As discussed at “Neuroinflammation in Diseases of the Central Nervous System,” a Keystone meeting held January 25-30 in Taos, New Mexico, the rabble-rousing signals that fire up microglia are not confined to the brain but also come from “below the neck,” said Hugh Perry of the University of Southampton in England. Whether triggered by acute infections or chronic disease, systemic inflammation may amplify microglial responses and exacerbate neurodegeneration, according to researchers at the meeting. They proposed ways to slow disease progression by soothing systemic inflammation.

The human body accumulates inflammatory battle scars as we age, whether through repeated assaults by microbial infections or chronic inflammatory diseases such as diabetes or atherosclerosis. Considering how systemic inflammation might alter the course of neurodegeneration is thus crucial, Perry said. “Old brains are attached to old bodies, and bodies tend to accumulate a lot of pathology over the years,” he said. At the meeting, Perry reported that this pathology primes microglia, making them prone to overreactions that could exacerbate neurodegeneration.

Sublime Microglia: Expanding Roles for the Guardians of the CNS: Cell

Recent findings challenge the concept that microglia solely function in
disease states in the central nervous system (CNS). Rather than simply
reacting to CNS injury, infection, or pathology, emerging lines of
evidence indicate that microglia sculpt the structure of the CNS, refine
neuronal circuitry and network connectivity, and contribute to
plasticity. These physiological functions of microglia in the normal CNS
begin during development and persist into maturity. Here, we develop a
conceptual framework for functions of microglia beyond neuroinflammation
and discuss the rich repertoire of signaling and communication motifs
in microglia that are critical both in pathology and for the normal
physiology of the CNS.

Microglial Magic: Drug Wipes Them Out, New Set Appears | ALZFORUM

Scientists are intensely interested in understanding the role
neuroinflammation plays in neurodegenerative disease. In the April 16
Neuron, researchers led by Kim Green at the University of California,
Irvine, provide a powerful new tool for doing so. Green and colleagues
reported that a small molecule inhibitor eliminated virtually all
microglia from the brains of wild-type mice, dousing ongoing
inflammation. The mice remained healthy and active for at least two
months, and even learned some cognitive tests faster than controls. Once
the inhibitor was withdrawn, microglia rapidly repopulated the brain,
returning to normal numbers within two weeks. Surprisingly, these
microglia appeared to arise from progenitor cells scattered throughout
the brain, rather than entering from the peripheral bloodstream as some
previous studies had found. If confirmed, this would represent the first
identification of a microglial progenitor in brain. “This has the
potential to be the largest, most widespread stem cell pool in the
brain,” Green told Alzforum.

Here's the paper:-

Colony-Stimulating Factor 1 Receptor Signaling Is Necessary for Microglia Viability, Unmasking a Microglia Progenitor Cell in the Adult Brain

Cancer drugs block dementia-linked brain inflammation, study finds -- ScienceDaily

A class of drugs developed to treat immune-related conditions and cancer
-- including one currently in clinical trials for glioblastoma and
other tumors -- eliminates neural inflammation associated with
dementia-linked diseases and brain injuries, according to researchers.
In their study, the researchers discovered that the drugs, which can be
delivered orally, eradicated microglia, the primary immune cells of the
brain. These cells exacerbate many neural diseases, including
Alzheimer's and Parkinson's, as well as brain injury.

Urban air pollution exposure may trigger toxic responses in brain cells and impact neurodegenerative disease pathways

According to Block, her team's work shows that many components of
urban air pollution, including the particle components of air pollution,
also called particulate matter, and gases, such as ground level ozone,
activate microglia.
Some of the problems with this cell type come in when the same
molecular tools used by microglia internalize (eat) and clean up toxic
stimuli and accidentally trigger the switch to an excessive, angry
activation state. The work she presented reveals how air pollution does
this, essentially leaving microglia with much more than a mouthful. Her
lab has discovered that the MAC1 pattern recognition receptor may be a
common mechanism through which microglia detect and ultimately
misinterpret different forms of air pollutionas an invading pathogen to result in excessive production of reactive oxygen species and consequent damage to neighboring brain cells.


Further, ongoing research in Block's lab aims to define where damage
to the lungs through inhaled toxicants produces injury signals in the
circulation that are not only detected by microglia in the brain, but
are responsible for shifting microglia to a deleterious phenotype
impacting central nervous system health. She refers to this as a
"Lung-Brain Axis."

Dynamic microglial alterations underlie stress-induced depressive-like behavior and suppressed neurogenesis: Mol Psych

The limited success in understanding the pathophysiology of major depression may result from excessive focus on the dysfunctioning of neurons, as compared with other types of brain cells. Therefore, we examined the role of dynamic alterations in microglia activation status in the development of chronic unpredictable stress (CUS)-induced depressive-like condition in rodents. We report that following an initial period (2–3 days) of stress-induced microglial proliferation and activation, some microglia underwent apoptosis, leading to reductions in their numbers within the hippocampus, but not in other brain regions, following 5 weeks of CUS exposure. At that time, microglia displayed reduced expression of activation markers as well as dystrophic morphology. Blockade of the initial stress-induced microglial activation by minocycline or by transgenic interleukin-1 receptor antagonist overexpression rescued the subsequent microglial apoptosis and decline, as well as the CUS-induced depressive-like behavior and suppressed neurogenesis. Similarly, the antidepressant drug imipramine blocked the initial stress-induced microglial activation as well as the CUS-induced microglial decline and depressive-like behavior. Treatment of CUS-exposed mice with either endotoxin, macrophage colony-stimulating factor or granulocyte-macrophage colony-stimulating factor, all of which stimulated hippocampal microglial proliferation, partially or completely reversed the depressive-like behavior and dramatically increased hippocampal neurogenesis, whereas treatment with imipramine or minocycline had minimal or no anti-depressive effects, respectively, in these mice. These findings provide direct causal evidence that disturbances in microglial functioning has an etiological role in chronic stress-induced depression, suggesting that microglia stimulators could serve as fast-acting anti-depressants in some forms of depressive and stress-related conditions.

Beyond Neighborhood Watch—Microglia Nurture Synapses | ALZFORUM

Besides patrolling the brain for tissue damage and other emergencies, microglia also help with routine maintenance, according to new research in the December 19 Cell. In adult mice engineered to lose microglia on demand, Wenbiao Gan, New York University School of Medicine, New York, and colleagues showed that the brain-resident immune cells facilitate synaptic plasticity. Mice lacking microglia performed poorly on several learning tasks. What’s more, ridding microglia of a single molecule—brain-derived neurotrophic factor (BDNF)—largely recapitulated the effects of depleting the brain phagocytes altogether.

The microglial sensome revealed by direct RNA sequencing : Nature Neuroscience : Nature Publishing Group

 Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings using fluorescence dual in situ hybridization, unbiased proteomic analysis and quantitative PCR. We found that microglia have a distinct transcriptomic signature and express a unique cluster of transcripts encoding proteins for sensing endogenous ligands and microbes that we refer to as the sensome. With aging, sensome transcripts for endogenous ligand recognition were downregulated, whereas those involved in microbe recognition and host defense were upregulated. In addition, aging was associated with an overall increase in the expression of microglial genes involved in neuroprotection.

Microglia play a major role in direct viral-induced demyelination.

 Microglia are the resident macrophage-like populations in the central nervous system (CNS). Microglia remain quiescent, unable to perform effector and antigen presentation (APC) functions until activated by injury or infection, and have been suggested to represent the first line of defence for the CNS. Previous studies demonstrated that microglia can be persistently infected by neurotropic mouse hepatitis virus (MHV) which causes meningoencephalitis, myelitis with subsequent axonal loss, and demyelination and serve as a virus-induced model of human neurological disease multiple sclerosis (MS). Current studies revealed that MHV infection is associated with the pronounced activation of microglia during acute inflammation, as evidenced by characteristic changes in cellular morphology and increased expression of microglia-specific proteins, Iba1 (ionized calcium-binding adaptor molecule 1), which is a macrophage/microglia-specific novel calcium-binding protein and involved in membrane ruffling and phagocytosis. During chronic inflammation (day 30 postinfection), microglia were still present within areas of demyelination. Experiments performed in ex vivo spinal cord slice culture and in vitro neonatal microglial culture confirmed direct microglial infection. Our results suggest that MHV can directly infect and activate microglia during acute inflammation, which in turn during chronic inflammation stage causes phagocytosis of myelin sheath leading to chronic inflammatory demyelination.

Can Network Analysis Identify Pathological Pathways in Alzheimer’s - AlzForum Alzheimer Research Live Discussions

: "In the April 25 Cell, Valur Emilsson at the Icelandic Heart Association and Eric Schadt at Icahn School of Medicine at Mount Sinai, New York, report that they have identified molecular networks that are perturbed in Alzheimer’s disease patients compared to normal, age-matched controls. Several of these networks comprise genes previously linked to AD, including TREM2 and CD33. The scientists also identified a new player, TYROBP, as a master regulator of these molecular modules. Meanwhile, in the April 25 Neuron, researchers led by Rudy Tanzi and Ana Griciuc at Massachusetts General Hospital, Charlestown, report that microglia in the AD brain overproduce CD33, which seems to prevent these cells from binding to and degrading amyloid-β. Together, these findings tighten the link between AD pathology and microglial dysfunction."

New findings on the brain's immune cells during Alzheimer's disease progression

 "The plaque deposits in the brain of Alzheimer's patients are surrounded by the brain's own immune cells, the microglia. This was already recognized by Alois Alzheimer more than one hundred years ago. But until today it still remains unclear what role microglia play in Alzheimer's disease. Do they help to break down the plaque deposit? A study by researchers of the Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch and Charité -- Universitätsmedizin Berlin has now shed light on these mysterious microglia during the progression of Alzheimer's disease."

Study examines role of microglial cells as both defenders and fighters in the nervous system

(Medical Xpress)—In many pathologies of the nervous system, there is a common event - cells called microglia are activated from surveillant watchmen into fighters.  Microglia are the immune cells of the nervous system, ingesting and destroying pathogens and damaged nerve cells. Until now little was known about the molecular mechanisms of microglia activation despite this being a critical process in the body.

Read more at: http://medicalxpress.com/news/2012-10-role-microglial-cells-defenders-fighters.html#jCp