Will Eradicating Microglia and Stopping Neuroinflammation Help in Autism?
By Teresa Conrick
I continue to explore many types of research to see what might be helpful for so many of our children affected by the insidious symptoms of neuroimmune disease, that many call AUTISM. Much research is pointing to the gut-brain axis, the microbiome and those effects on development. This is not a new concept but one that needs much more attention.
I recently saw this medical article in the news:
Cancer drugs block dementia-linked brain inflammation, study finds
Date: April 16, 2014
Source: University of California - Irvine
Summary:
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.
This summary from the abstract of the actual study - Colony-Stimulating Factor 1 Receptor Signaling Is Necessary for Microglia Viability, Unmasking a Microglia Progenitor Cell in the Adult Brain
The colony-stimulating factor 1 receptor (CSF1R) is a key regulator of myeloid lineage cells. Genetic loss of the CSF1R blocks the normal population of resident microglia in the brain that originates from the yolk sac during early development. However, the role of CSF1R signaling in microglial homeostasis in the adult brain is largely unknown. To this end, we tested the effects of selective CSF1R inhibitors on microglia in adult mice. Surprisingly, extensive treatment results in elimination of ∼99% of all microglia brain-wide, showing that microglia in the adult brain are physiologically dependent upon CSF1R signaling. Mice depleted of microglia show no behavioral or cognitive abnormalities, revealing that microglia are not necessary for these tasks. Finally, we discovered that the microglia-depleted brain completely repopulates with new microglia within 1 week of inhibitor cessation. Microglial repopulation throughout the CNS occurs through proliferation of nestin-positive cells that then differentiate into microglia.
Since microglia are heavily involved in autism, I am curious if this research would apply to autism and have benefits to the thousands of individuals, mostly kids, affected?
Microglial activation in young adults with autism spectrum disorder.
Brain imaging study points to microglia as autism biomarker
Microglia in the Cerebral Cortex in Autism
Brain's immune cells show intriguing links to autism
From one of the study authors:
"Because microglia are implicated in most brain disorders, we feel we've found a novel and broadly applicable therapeutic approach," Green said. "This study presents a new way to not just modulate inflammation in the brain but eliminate it completely, making this a breakthrough option for a range of neuroinflammatory diseases."
I have to point out that because the gut and the immune system are also implicated in autism, will eliminating microglia solve the biggest issue of autism?
Would love to hear opinions on this so please leave a comment.
Teresa Conrick is Contributing Editor to Age of Autism.
Dr. Mario Capecchi, a University of Utah geneticist who researches the cause of OCD behavior in mice. He said decfective microglia are what cause OCD and other disorder like autism. He says "Defective microglia output defective behavior"
I think we are seeing an over active response of the microglia but the micrologial cells are charged by mitochondria. So if mitochondria are not working right nor will the microglia. The cell is programmed to die.
Microglia are part of the brains immune system so it would not make sense to eradicate them. They are involved in fighting infections and pruning synapses. Something in the cell is going haywire leading to dysfunction of the microglia.
In examining postmortem brains Pardo found the microglia appeared "angry". (see link for photo microglia in the postmortem brain of a child with autism compared to a normal brain. The microglia indeed look shriveled.
"Molecular mechanisms: Autism brains show 'angry' microglia" - SFARI web site
https://sfari.org/news-and-opinion/in-brief/2010/molecular-mechanisms-autism-brains-show-activated-immune-defense
I think the problem with these "angry" looking microglia all goes back to mitochondrial dysfunction. The mitochondria in the microglial cells are being chemically induced to overreact leading to a microglial dysfunction - the cell burns out and becomes damaged- this manifest as a host of behaviors from OCD to Schizophrenia to autism.
Dr. Cappecchi work is groundbreaking and he explain the link between micrglia and mental illness so well.
"Utah Scientist Makes Breakthrough In Mental Illness Research" -KSL tv
http://www.ksl.com/?sid=10947928
Posted by: autismmom | May 08, 2014 at 09:20 AM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3381634/
Blaylock is not the only one saying there is the destructive and then there is the restoring kind of microglia
It will not be that simple to just stop it or destroy it.
Quotes here:
"We have seen that microglia have important physiological functions on the normal CNS and a dual role after neural disorders. How to explain this apparent paradox? In the following paragraphs, based on experimental evidences, including our own data, we propose a hypothesis to explain the dual role of microglia after CNS diseases.-----"
"In this paper, we shed light on the possible reasons by which microglia can be both detrimental and beneficial after CNS diseases. We face microglia as the guardians of CNS, which contribute to maintenance of its integrity in physiological conditions. In pathological conditions, some microglial cells might be affected by the disease process becoming overactivated contributing to neuronal damage, whereas others might maintain an intermediate (more physiological) level of activation contributing to neuronal rescue and repair processes. This might be a consequence of the fact that both harmful and beneficial stimuli are released upon injury into specific anatomical niches along the damaged areas triggering both beneficial and deleterious actions of microglia. Depending on the CNS-affected area and disease's etiology, both noxious and beneficial microglial phenotypes might coexist along the pathological environment."
" It is also fundamental to find out which microglia receptors are specifically activated to induce beneficial or detrimental actions after a CNS disease. Experimental manipulation of these receptors, and/or pharmacological application of their beneficial ligands, may be promising therapeutic approaches used in the future for human neural disorders."
Posted by: Benedetta | May 08, 2014 at 12:52 AM
I think Dr. Blaylock explains that microglia has not only an active phase but also has a resting stage.
In the active stage they are destroying, In the resting stage they repair the damage.
Microglia stimulation also stimulates astrocytes which also can damage the brain -- but again astrocytes when not in this inflammation stage will restore and repair the damage that has occurred to the brain. Microglia -I am not sure about this - inhances the astrocytes in what ever phaae they are int?? Well in the destructive phase for sure.
So I have to wonder if shutting down the microglila completely - would then mean no repair either.
Posted by: Benedetta | May 07, 2014 at 11:24 PM
Yes, I think that there is a reason for the presence of microglia, so eliminating it permanently might not be a great solution all the time. But might it be used in the worst cases, when a situation becomes uncontrollable or physically dangerous, like poor Alex Sp., to bring things under control, instead of trying only psych drugs? I thought one of the articles she linked to, though, talked about transplanting somehow with healthy microglia, as opposed to just letting them grow back. Maybe I misread?
Re: the cancer drug after the anti-nmda enceph. article. Hearing about this doesn't really surprise me. There was an article maybe a year ago or so about out in California a drug that looked promising for helping autism symptoms. The very last line of the article mentioned that the drug had antineoplastic properties. Wow did that catch my attention, as I had just been discussing autism with a homeopath and the topic of miasms came up. I mentioned some stuff about syphilis treatment ideas in the book Age of Autism, wondering if there were connections to the syphilis miasm characteristics, but the gentleman I spoke w/had heard autism discussed, rather, in the context of cancer miasm.
So there are folks out there that might easily see why a cancer treatment might affect someone with autistic-like manifestations.
Posted by: Jenny | May 07, 2014 at 10:47 PM
Hi Dan,
Thanks for the chuckle! Yes, checking this stuff out is helpful to examine both the good and bad consequences.
Watch your toes!
Posted by: Teresa Conrick | May 07, 2014 at 10:03 PM
Teresa and everybody,
I’d love to see an “Awakening” for our kids, too. Not to be anti-science, but I read the Neuron abstract and associated research with waning enthusiasm. Here’s a little humorous dose of skepticism on CSF1R inhibitors.
ME: Doc, my toes are swollen. They hurt.
DOC SYMPTOM-BE-GONE: Take this pill and they’ll die and drop off.
ME: But I need my toes!
DOC SYMPTOM-BE-GONE: For what? Toeless mice are just as smart as whole mice. Even smarter! And their toes grow back.
ME: Would you take that pill?
DOC SYMPTOM-BE-GONE: Of course not. But my toes don’t hurt.
All with good will, Teresa. Keep up the good work ;)
Posted by: Dan Burns | May 07, 2014 at 08:06 PM
Eradicate microglia? Probably couldn't. See article --
"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 . . . "
Posted by: AutAutAut | May 07, 2014 at 05:29 PM
What is causing the microglia to dysfunction? I have to wonder what the relationship is between microglia and mitochondrial dysfunction which many kids with autism have been found to have.
I went online found this study that links the two:
Journal of Neuroinflammation 2010, 7:45 doi:10.1186/1742-2094-7-45
"Effects of mitochondrial dysfunction on the immunological properties of microglia"
Annette I Ferger, Loretta Campanelli, Valentina Reimer, Katharina N Muth, Irma Merdian, Albert C Ludolph and Anke Witting*
Abstract
Background
Neurodegenerative diseases are characterized by both mitochondrial dysfunction and activation of microglia, the macrophages of the brain. Here, we investigate the effects of mitochondrial dysfunction on the activation profile of microglial cells.
Methods
We incubated primary mouse microglia with the mitochondrial toxins 3-nitropropionic acid (3-NP) or rotenone. These mitochondrial toxins are known to induce neurodegeneration in humans and in experimental animals. We characterized lipopolysaccharide- (LPS-) induced microglial activation and the alternative, interleukin-4- (IL-4-) induced microglial activation in these mitochondrial toxin-treated microglial cells.
Results
We found that, while mitochondrial toxins did not affect LPS-induced activation, as measured by release of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6) and interleukin-1β (IL-1β), they did inhibit part of the IL-4-induced alternative activation, as measured by arginase activity and expression, induction of insulin-like growth factor 1 (IGF-1) and the counteraction of the LPS induced cytokine release.
Conclusions
Mitochondrial dysfunction in microglial cells inhibits part of the IL-4-induced alternative response. Because this alternative activation is considered to be associated with wound healing and an attenuation of inflammation, mitochondrial dysfunction in microglial cells might contribute to the detrimental effects of neuroinflammation seen in neurodegenerative diseases.
full study: http://www.jneuroinflammation.com/content/7/1/45
Below is a very interesting interview with geneticist Dr. Mario Capecchi I have posted before on the relationship between microglia and mental illness:
Utah scientist makes breakthrough in mental illness research
Read more at http://www.ksl.com/?nid=148&sid=10947928#6VB9pchPLe8mXo3R.99
http://www.ksl.com/?sid=10947928
Posted by: autismmom | May 07, 2014 at 03:29 PM
Teresa;
I know we all have listened to Dr. Blaylock on microglia, many times --
but maybe a review of what he says about it will help
https://www.youtube.com/watch?v=uS0ioiB0_oY
How infection kills us -is not the virus but the reaction of the immune system of the brain is what does us in.
Posted by: Benedetta | May 07, 2014 at 01:38 PM
Hi Teresa,
While the study of Microglia is fascinating in regards to autism and there is some potential in harnessing what we know (or learning more) to treat (and I say this with a grain of salt, because many autists or parents of autists see nothing to treat) autism via microglia, It would probably not be as black and white as eliminating microglia.
Microglia are integral in normal synaptic pruning processes during post natal development (0-12 months). Very basically, the human brain makes many synaptic connections (connections between neurons) during activity dependent development. During development neurons make an overabundance of synaptic connections and the weakest or least used connections have to be pruned away, this is the job of the microglia.
What is interesting is that there is mounting evidence that disruption of this normal pruning process may be an important factor in the development of autism, resulting in dysfunctional neuronal connectivity (i.e. too many short range connections, weak connections, improper connections, etc.)
That being said, it would not be good to eliminate microglia during this crucial time of synapse remodeling. However, it may be beneficial to effectively modulate microglia during this time as it is apparent that microglia can exist in a range of states from active to surveillance (once thought as resting), which obviously affects their functionality.
As our understanding of the role of microglia in both pathogenic and normal processes increases, we will be able to better assess whether there are avenues to modify these processes for therapeutic value.
One has to remember that science moves rather slowly and it takes time to just develop a basic understanding of how, say microglia, work in the human body. I'm talking countless hours of experimentation and animal modeling by numerous different research groups. Once some of the basic research and knowledge accumulates (it is accumulating as I write this), then scientists will be able to refine approaches and hypotheses to test possible therapeutic interventions.
hope this helps!
Skeptiquette
Posted by: Skeptiquette | May 07, 2014 at 12:56 PM
I hope some doctors and researchers who work with autism go to that conference to learn and share information. Maybe it can bring us closer to finding new solutions for our kids.
Posted by: AutismGoAway | May 07, 2014 at 11:31 AM
Lisa,That article was amazing. Many of our kids suffer dramatic regressions but are just told to do ABA. There is something wrong with this approach. I feel like our children 's situations are not being taken seriously.
Posted by: AutismGoAway | May 07, 2014 at 11:29 AM
I saw this article in the Washington Post last week. It may or may not be relevant. I commented on the article because it sounded to me like this teen may have been suffering from vaccine-induced encephalitis. Treatment was a cancer drug. It worked and she is cured.
http://www.washingtonpost.com/national/health-science/the-doctor-and-the-teenager/2014/04/28/e92eadaa-98b2-11e3-b931-0204122c514b_story.html
Posted by: lisa | May 07, 2014 at 10:55 AM
Thank you, Dr. Mary Maxwell. I appreciate the support! Here is an interesting conference that I sort of stumbled upon and think both the autism community and the pandas community would benefit.
http://www.eventbrite.com/e/the-microbiome-and-autoimmune-disease-colloquium-tickets-10909325085
The Microbiome and Autoimmune Disease Colloquium
A Noel R. Rose Colloquium on Autoimmunity
May 16-18th, 2014
National Conference Center - 18980 Upper Belmont Place - Leesburg, VA
This symposium is hosted by the American Autoimmune Related Diseases Association, in collaboration with the Society for Women’s Health Research and the Immune Deficiency Foundation.
This scientific meeting is part of a continuing effort to encourage collaboration in the areas of autoimmune disease and inflammation. The conference will assemble a diverse group of scientists from a variety of specialties to discuss emerging research in immunology, the microbiome and influence of the environment.
Friday, May 16, 2014 - 7:00pm - 8:30pm
Welcome Reception:
Andrew Serazin, Speaker - President and CEO of Matatu, Inc and Senior Fellow in Global Health, University of Oxford
Confirmed Speakers - Saturday, May 17th, 2014:
Begins at 8:30am. Lunch is provided.
Measuring Environmental Influence on Immune Diseases
Dr. John Bienenstock - McMaster University, Hamilton, Ontario
Dr. Marian J. Rewers - University of Colorado, Denver
Dr. Eugene Chang – University of Chicago
Dr. Charles Bernstein - University of Manitoba
Dr. Gregory F. Sonnenberg - Penn Institute for Immunology
The Microbiome and Immune Disease
Dr. Joseph A. Murray - Mayo Clinic
Dr. Gary D. Wu – University of Pennsylvania
Dr. Jonathan Braun - UCLA Pathology
Dr. Javier Ochoa-Repáraz – University of California, Santa Barbara
Dr. Jens Walter - University of Alberta, Edmonton, Canada
Sex Differences in the Microbiome
Dr. Robert H. “Hal” Scofield - Oklahoma Medical Research Fndn
Dr. Alexander Chervonsky - The University of Chicago
Dr. Omry Koren - Galilee Bar-Ilan University, Israel
Dr. Lisa Kilpatrick – University of California, Los Angeles
Dr. Sumathi Sankaran-Walters – University of California, Davis
Colloquium Day ends at 5:30pm.
Confirmed Speakers - Sunday - May 18th, 2014:
Begins at 8:30am. Lunch is provided.
Impacts of the Microbiota on Autoimmune Disease
Dr. Daniel Peterson - Johns Hopkins University
Dr. Lloyd Kasper – Dartmouth University
Dr. Veena Taneja – Mayo Clinic
Dr. Rachel Caspi - National Eye Institute
Dr. Iliyan Iliev- Cedars-Sinai Hospital
Colloquium Day ends at 11:30am.
Posted by: Teresa Conrick | May 07, 2014 at 10:30 AM
Dear Teresa, Your asking for help made me think of the story of the great Shakespeare scholar, George Lyman Kittredge, asking the librarian at the Bodleian for some information on the bard. She replied “We don’t know. Perhaps the only one who could help you is Kittredge at Harvard.”
(Seriously, Ms Conrick, you are the expert, isn’t that awful? You know what I mean.)
Anyway, your earlier work on the biome caused me to go searching, and so now I can bring you a couple of coals from Newcastle:
First, JL Round and SK Mazmanian, back in May, 2009, in National Review of Immunology, raised “the possibility that the mammalian immune system, which seems to be designed to control microorganisms, is in fact controlled by microorganisms.” Holy Toledo. Could this mean that the environmental trigger of autism is food? (Besides the obvious thought of the content of vaccines…)
Second, C Basset and J Holton had pointed out in 2002, in an article in Science Progress (85 Part I), that:
“The cause(s) of Irritable Bowel Disease, IBD, are currently unknown but the mechanisms of injury are immunological. …Several genetic loci that are markers of disease susceptibility have been identified. These loci map to areas of the genome concerned with antigen presentation or cytokine secretion…. A picture is emerging of defects in epithelial barrier function … leading to immune responses triggered by antigenic components of normal flora.”
Normal flora! Fancy that. And they "know" that the mechanisms of injury are immunological. Kind of a well-kept secret, I’d say.
Thanks a million for yelling about the biome, Teresa. You are hot on the trail. And getting hotter!
Posted by: Mary W Maxwell, PhD, LLB | May 07, 2014 at 09:40 AM
Are there any side effects of theses drugs? Risks? How long have they been used with cancer? Have they ever been used on children? is there someone willing to do clinical trials with autism? Would they include severe autism and older children and adults in their studies? Thank you for posting this! There are so many many kids/adults suffering right now. I would love to see another "Awakenings". I don't believe our children have permanent brain damage. Miracles are possible ... Where there is a will...
Posted by: AutismGoAway | May 07, 2014 at 06:18 AM