The Brain’s Gardeners: Immune Cells ‘Prune’ Connections Between Neurons
A new study, published in the journal Nature Communications,
shows that cells normally associated with protecting the brain from
infection and injury also play an important role in rewiring the
connections between nerve cells. While this discovery sheds new light
on the mechanics of neuroplasticity, it could also help explain diseases
like autism spectrum disorders, schizophrenia, and dementia, which may
arise when this process breaks down and connections between brain cells
are not formed or removed correctly.
Microglia (green) with purple representing the P2Y12 receptor which the
study shows is a critical regulator in the process of pruning
connections between nerve cells)
“We have long considered the reorganization of the brain’s network of connections as solely the domain of neurons,” said Ania Majewska, Ph.D., an associate professor in the Department of Neuroscience
at the University of Rochester Medical Center (URMC) and senior author
of the study. “These findings show that a precisely choreographed
interaction between multiple cells types is necessary to carry out the
formation and destruction of connections that allow proper signaling in
The study is another example of a dramatic shift in
scientists’ understanding of the role that the immune system,
specifically cells called microglia, plays in maintaining brain
function. Microglia have been long understood to be the sentinels of
the central nervous system, patrolling the brain and spinal cord and
springing into action to stamp out infections or gobble up dead cell
tissue. However, scientists are now beginning to appreciate that, in
addition to serving as the brain’s first line of defense, these cells
also have a nurturing side, particularly as it relates to the
connections between neurons.
The formation and removal of the
physical connections between neurons is a critical part of maintaining a
healthy brain and the process of creating new pathways and networks
among brain cells enables us to absorb, learn, and memorize new
“The brain’s network of connections is like a
garden,” said Rebecca Lowery, a graduate student in Majewska’s lab and
co-author of the study. “Not only does it require nourishment and a
healthy environment, but every once in a while you need to prune dead
branches and pull up weeds in order to allow new flowers to grow.”
this constant reorganization of neural networks – called
neuroplasticity – has been well understood for some time, the basic
mechanisms by which connections between brain cells are made and broken
has eluded scientists.
Performing experiments in mice, the
researchers employed a well-established model of measuring
neuroplasticity by observing how cells reorganize their connections when
visual information received by the brain is reduced from two eyes to
The researchers found that in the mice’s brains microglia
responded rapidly to changes in neuronal activity as the brain adapted
to processing information from only one eye. They observed that the
microglia targeted the synaptic cleft – the business end of the
connection that transmits signals between neurons. The microglia
“pulled up” the appropriate connections, physically disconnecting one
neuron from another, while leaving other important connections intact.
is similar to what occurs during an infection or injury, in which
microglia are activated, quickly navigate towards the injured site, and
remove dead or diseased tissue while leaving healthy tissue untouched.
researchers also pinpointed one of the key molecular mechanisms in this
process and observed that when a single receptor – called P2Y12 – was
turned off the microglia ceased removing the connections between
These findings may provide new insight into disorders
that are the characterized by sensory or cognitive dysfunction, such as
autism spectrum disorders, schizophrenia, and dementia. It is possible
that when the microglia’s synapse pruning function is interrupted or
when the cells mistakenly remove the wrong connections – perhaps due to
genetic factors or because the cells are too occupied elsewhere fighting
an infection or injury – the result is impaired signaling between brain
“These findings demonstrate that microglia are a dynamic
and integral component of the complex machinery that allows neurons to
reorganize their connections in the healthy mature brain,” said Grayson
Sipe, a graduate student in Majewska’s lab and co-author of the study. “While more work needs to be done to fully understand this process, this
study may help us understand how genetics or disruption of the immune
system contributes to neurological disorders.”
Migrating immune cells promote nerve cell demise in the brain
The slow death of dopamine-producing nerve cells in a certain region of the brain is the principal cause underlying
Parkinson’s disease. In mice, it is possible to simulate the symptoms of
this disease using a substance that selectively kills
dopamine-producing neurons. Scientists from the German Cancer Research
Center (DKFZ) have now shown for the first time in mouse experiments
that after this treatment, cells of the peripheral immune system migrate
from the bloodstream into the brain, where they play a major role in
the death of neurons. The investigators were able to reduce the level of
neurodegeneration using a substance that blocks a specific surface
molecule on these inflammatory cells.
A small area in the midbrain known as
the substantia nigra is the control center for all bodily movement.
Increasing loss of dopamine-generating neurons in this part of the brain
therefore leads to the main symptoms of Parkinson’s disease – slowness
of movement, rigidity and shaking.
In recent years, there has been increasing
scientific evidence suggesting that inflammatory changes in the brain
play a major role in Parkinson’s. So far, it has been largely unclear
whether this inflammation arises inside the brain itself or whether
cells of the innate immune system that enter the brain from the
bloodstream are also involved.
At the DKFZ, a team led by Prof. Dr. Ana
Martin-Villalba is investigating causes of cell death in the central
nervous system. Neuroscientist Martin-Villalba has suspected that a
specific pair of molecules, the CD95 system, is involved in neuronal
death in Parkinson’s. This pair consists of the CD95 ligand and its
corresponding receptor, CD95, also known as the “death receptor”.
Martin-Villalba recently showed that after spinal
cord injury, inflammatory cells use these molecules to migrate to the
injury site, where they cause damage to the tissue. Martin-Villalba then
wanted to investigate whether peripheral inflammatory cells also play a
role in chronic neurodegenerative processes such as Parkinson’s
To investigate the process of neurodegeneration in
mice, the scientists utilized a model system using the substance MPTP,
which causes the selective death of dopamine-generating neurons in the
human brain. In mice, MPTP typically causes Parkinson-like symptoms.
However, in mice whose inflammatory cells
(monocytes, microglia) were unable to produce CD95L, MPTP treatment
resulted in almost no neurodegeneration. This suggested that
CD95L-bearing inflammatory cells are involved in the destruction of
neurons. However, it remained unclear whether the true culprits are
specific macrophages in the brain called microglia, or rather monocytes
in the bloodstream that infiltrate the brain.
In order to make this distinction, the
investigators used a chemical that blocks CD95L without being able to
pass the blood-brain barrier. This substance therefore reaches only the
inflammatory cells that circulate in the bloodstream and not the
microglia that reside in the brain. Mice that had received this
substance were also protected from MPTP-induced neurodegeneration.
“Thus, we have shown for the first time that
peripheral inflammatory cells of the innate immune system also play a
role in neurodegeneration,” say Liang Gao and David Brenner, first
authors of the publication. “A key role in this process is played by
CD95L, which enhances the mobility of these cells.”
Project leader Martin-Villalba speculates that a
self-reinforcing vicious cycle arises in the brain: The breakdown of a
few neurons that die from various causes attracts inflammatory cells
that, in turn, further fuel the death of more neurons through
inflammation-promoting signaling molecules.
At present, the researchers can only indirectly
conclude that the results obtained in the artificial animal model are
also relevant in human Parkinson’s disease. In collaboration with
colleagues from Ulm, Martin-Villalba’s team recently found elevated
quantities of inflammatory monocytes that were hyperactive in blood
samples from Parkinson’s patients. Monocyte number correlated with the
severity of disease symptoms. However, the researchers do not yet know
whether these inflammatory cells also migrate into the brains of
patients and contribute to the demise of neurons there, like they do in
the mice with Parkinson’s.
“If this is the case, drugs that inhibit CD95L
might mitigate Parkinson’s symptoms if administered early on – similar
to what we observed in our experimental mice,” says Martin-Villalba. The
substance required for this has already been investigated in clinical
Phase II trials. Martin-Villalba also suspects that activated cells of
the peripheral immune system might drive neurodegeneration not only in
Parkinson’s disease but also in other neurodegenerative disorders such
At present, researchers know very little about exactly how microglia work. At the same time, there is a lot of curiosity and high hopes among brain researchers that greater understanding of microglia could lead to entirely new drug development strategies for various brain diseases”, says Johan Jakobsson, research group leader at the Division of Molecular Neurogenetics at Lund University.
What the researchers have now succeeded in identifying is a deviation in the structure of the microglia cells, which makes it possible to visualise them and study their behaviour. By inserting a luminescent protein controlled by a microscopic molecule, microRNA-9, the researchers can now distinguish the microglia and monitor their function over time in the brains of rats and mice.
It has long been known that microglia form the first line of defence of the immune system in diseases of the brain. They move quickly to the affected area and release an arsenal of molecules that protect the nerve cells and clear away damaged tissue.
New research also suggests that microglia not only guard the nerve cells but also play an important role in their basic function.
“This represents a real step forward in technological development. Now we can view microglia in a way that has not been possible before. We and our colleagues now hope to be able to use this technique to study the role of the cells in different disease models, for example Parkinson’s disease and stroke, in which microglia are believed to play an important role”, explains Johan Jakobsson.
Microglia Can Be Derived From Patient-Specific Human Induced Pluripotent Stem Cells and May Help Modulate the Course of Central Nervous System Diseases
Today, during the 81st American Association of Neurological Surgeons (AANS) Annual Scientific Meeting, researchers announced new findings regarding the development of methods to turn human induced pluripotent stem cells (iPSC) into microglia, which could be used for not only research but potentially in treatments for various diseases of the central nervous system (CNS).
Microglia are the resident inflammatory cells of the CNS and can modulate the outcomes of a wide range of disorders including trauma, infections, stroke, brain tumors, and various degenerative, inflammatory and psychiatric diseases. However, the effective therapeutic use of microglia demonstrated in various animal CNS disease models currently cannot be translated to patients due to the lack of methods for procuring high-purity patient-specific microglia. Developing a method for obtaining these cells would be highly valuable.
In the study Differentiation of Induced Pluripotent Stem Cells to Microglia for Treatment of CNS Diseases, mouse and human iPSCs were generated and sequentially co-cultured on various cell monolayers and in the presence of added growth factors. The microglial identity of the resulting cells was confirmed using fluorescence activated cell sorting analyses, functional assays, gene expression analyses and brain engraftment ability. The study results will be shared by presenting author John K. Park, MD, PhD, FAANS, from 3:34-3:42 p.m. on Monday, April 29. Co-authors are Michael Shen, BS; Yong Choi, PhD; and Hetal Pandya, PhD.
In the results, researchers found mouse and human iPSCs co-cultured with OP9 cells differentiate into hematopoietic progenitor cells (HPCs). HPCs in turn co-cultured with astrocytes, generate cells that express CD11b, Iba-1 and CX3CR1; secrete the cytokines IL-6, IL-1ß and TNF-a; generate reactive oxygen species; and phagocytose fluorescent particles, all consistent with a microglial phenotype. Gene expression clustering using self-organizing maps indicates that iPSC-derived microglia more closely resemble normal microglia than other inflammatory cell types. The iPSC-derived microglia engraft and migrate to areas of injury within the brain. These finding have led researchers to conclude that iPSC-derived microglia may one day be useful as gene and protein delivery vehicles to the CNS.
“The actual results of our research were not surprising to us, but the overall importance of microglia in a wide variety of brain and spinal cord diseases was surprising. Microglia likely have a role in improving or worsening diseases such as multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, obsessive compulsive disorder and Rett’s syndrome, just to name a few,” said John K. Park, MD, PhD, FAANS. “Microglia are the principal immune system cells of the brain and spinal cord, and help fight infections as well as help the healing process after injuries such as trauma and strokes. They also play a poorly understood role in many neurodegenerative and psychiatric diseases. We have developed methods to turn iPSCs into microglia. Because human iPSC can easily be obtained in large numbers, we can now generate large numbers of human microglia not only for use in experiments, but also potentially for use in treatments. The ability to study normal and diseased human microglia will lead to a greater understanding of their roles in healthy brains and various diseases. Diseases that are caused or exacerbated by defective microglia or a paucity of normal microglia may potentially be treated by microglia generated from a patient’s iPSC.”