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Showing posts with label MS. Show all posts
Showing posts with label MS. Show all posts

Tuesday, 4 June 2019

Meningeal Lymphatics in Autism - at least two possibly relevant dysfunctions




  
I am always surprised how popular some posts with complicated titles are on this blog. Meningeal lymphatics in Bart Simpson speak would be “brain plumbing”.  Today we discover that:-

·        Immune cells can enter the brain by climbing up the brain’s plumbing pipes, entering originally via lymph nodes outside the brain

·        Those same plumbing pipes get blocked and waste is not free flowing out of the brain. The blockage may be at a brain-draining lymph node.

Today’s post follows up some research that I think Tyler highlighted a long time ago, about the recent discovery that the brain has its own lymphatic system.





                       
Human Lymphatic System before 2015              Human Lymphatic System after 2015




In a stunning discovery that overturns decades of textbook teaching, researchers at the University of Virginia School of Medicine have determined that the brain is directly connected to the immune system by vessels previously thought not to exist. That such vessels could have escaped detection when the lymphatic system has been so thoroughly mapped throughout the body is surprising on its own, but the true significance of the discovery lies in the effects it could have on the study and treatment of neurological diseases ranging from autism to Alzheimer's disease to multiple sclerosis.

Structural and functional features of central nervous system lymphatic vessels


Editorial Summary

A lymphatic system for the brain

The central nervous system is under constant immune surveillance, but the exit route for immune cells has been unclear as the brain was thought to lack a classical lymphatic drainage system. Jonathan Kipnis and colleagues now show that the brain does indeed possess functional lymphatic vessels, located in the meninges, and that these vessels are able to carry both fluid and immune cells from the cerebrospinal fluid. The presence of a classical lymphatic system in the central nervous system suggests that current thinking on brain tolerance and the immune privilege of the brain should be revisited. Malfunction of the meningeal lymphatic vessels could be a root cause of a variety of neuroimmunological disorders. 

  

Knowledge has moved on a bit further since 2015 and hence today’s post, but the research is focused on MS and Alzheimer’s rather than autism.

The lymphatic system carries a clear fluid call lymph.

The lymphatic system has multiple interrelated functions

·         It is responsible for the removal of interstitial fluid from tissues
·         It absorbs and transports fatty acids and fats as chyle from the digestive system
·         It transports white blood cells to and from the lymph nodes into the bones
·         The lymph transports antigen-presenting cells, such as dendritic cells, to the lymph nodes where an immune response is stimulated.

The discovery in 2015 - A lymphatic system for the brain

The central nervous system is under constant immune surveillance, but the exit route for immune cells has been unclear as the brain was thought to lack a classical lymphatic drainage system.

Jonathan Kipnis discovered that the brain does indeed possess functional lymphatic vessels, located in the meninges, and that these vessels are able to carry both fluid and immune cells from the cerebrospinal fluid. The presence of a classical lymphatic system in the central nervous system suggests that current thinking on brain tolerance and the immune privilege of the brain should be revisited. Malfunction of the meningeal lymphatic vessels could be a root cause of a variety of neuroimmunological disorders.






When a tissue is infected by a pathogen, like a virus, bacteria, or parasite, bits and pieces of the offending pathogen end up in the lymph. These pieces, along with immune cells from the infected tissue, reach the lymph node, and the cells in the lymph node then react to coordinate a specific immune response to the pathogen. Thus, the system not only allows for recirculation of bodily fluid, but it also provides a means for the immune system to sift through material from around the body in order to scan for infection. Without lymphatics, fluid would build up in body tissues, and there would be no way to alert the adaptive immune system to invading pathogens.


Alzheimer's, Autism, MS and Beyond

The unexpected presence of the lymphatic vessels raises a tremendous number of questions that now need answers, both about the workings of the brain and the diseases that plague it. For example, take Alzheimer's disease. "In Alzheimer's, there are accumulations of big protein chunks in the brain," Kipnis said. "We think they may be accumulating in the brain because they're not being efficiently removed by these vessels." He noted that the vessels look different with age, so the role they play in aging is another avenue to explore. And there's an enormous array of other neurological diseases, from autism to multiple sclerosis, that must be reconsidered in light of the presence of something science insisted did not exist

It is now suggested that several organs may be sites at which CNS-specific T cells become ‘licensed’ to acquire an appropriate migratory profile that will allow them to infiltrate the CNS.

What that means is an immune dysfunction far away from the brain and its blood brain barrier defences can send its messengers up the brain’s drain pipes and directly into the brain.

By closing the drain pipes you can prevent serious brain inflammation like that found in Multiple Sclerosis.

 Kipnis’ idea is to target major neurological disorders through therapeutic manipulation of peripheral structures, such as lymphatic vessels.  In other words, you block the inflammatory signals from entering the brain.

The research has now shown that this is indeed achievable in the mouse model of multiple sclerosis.

The problem with blocking the flow through the pipes is that you need them to be free flowing to avoid dementia and cognitive decline.  The Alzheimer’s research suggests that opening up the pipes wide to clear away accumulated junk in the brain might well stave off the disease.

The solution might involve some complex plumbing adjustment.

For old people it might be key to modify the lymphatic system inside the brain, so as to open those blocked pipes.  It may be that in some autism a variant of this problem also exists.  There is a section on this later in the post, with some case histories.
For people with MS and inflammatory-type autism it might be the case of closing the pipes at a clever location in the lymphatic system outside the brain to stop inflammatory messengers entering the lymph system and heading up into the brain. 

While autism research is rarely class-leading, MS research and Alzheimer’s research attracts plenty of smart scientists and research dollars.  This means that you may want to keep an eye on research in those two diseases.

Now we look at the research:

  • Multiple Sclerosis
  • Alzheimer’s
  • Autism


Multiple Sclerosis

Great strides are being made in MS research and some of the off-label therapies like Ibudilast, referred to in this autism blog, are showing promise in clinical trials.

Brain-draining lymph nodes exist outside the brain and you can actually measure how much CSF is flowing out of the brain.  In older brains the flow rate is much less, as if the drains have got clogged up. 

Brain-draining lymph nodes also allow inflammatory messengers to enter the central nervous system (CNS) that was supposed to be kept safe behind the blood brain barrier.

Brain's lymphatic vessels as new avenue to treat multiple sclerosis

Vessels carry mysterious message from brain that causes MS, research suggests

                          
Lymphatic vessels that clean the brain of harmful material play a crucial role in the development and progression of multiple sclerosis, new research from the University of Virginia School of Medicine suggests. The vessels appear to carry previously unknown messages from the brain to the immune system that ultimately trigger the disease symptoms. Blocking those messages may offer doctors a new way to treat a potentially devastating condition that affects more than 2 million people.
The discovery comes from the lab of UVA researchers who identified the lymphatic vessels surrounding the brain, vessels that textbooks long insisted did not exist. In an exciting follow-up, the researchers have determined that the vessels play an important role in not only multiple sclerosis but, most likely, many other neuroinflammatory diseases and in dangerous brain infections.
"Our data suggests that there is a signal coming from the brain to the lymph nodes that tells immune cells to get back into the brain, causing the [multiple sclerosis] pathology," said researcher Antoine Louveau, PhD, of UVA's Department of Neuroscience and its Center for Brain Immunology and Glia (BIG). "This is an important proof of principle that exploring the role of these vessels in different neurological disorders, including multiple sclerosis, is worth it."
Stopping Multiple Sclerosis
The researchers at UVA, led by Jonathan Kipnis, PhD, were able to impede the development of multiple sclerosis in mice by targeting the lymphatic vessels surrounding the brain. They used multiple strategies to block the lymphatics or destroy them with a precision laser. All led to the same outcome: a decrease in the number of destructive immune cells capable of causing paralysis.
"The idea was to prevent more widespread damage to the nervous system," said researcher Jasmin Herz. "If communication of brain inflammation through lymphatic vessels is the root cause of multiple sclerosis, therapies targeting these vessels could be clinically important."
The message from the brain that appears to drive multiple sclerosis remains poorly understood. The researchers can tell the message is being sent, and they can tell what it is instructing the immune system to do, but they don't yet know what mechanism the brain is using to send it. "I think the next step in this specific research is to identify what that signal is. Is it a cellular signal, is it a molecular signal?" Louveau said. "And then to try to target that signal specifically."
The researchers noted that removing the vessels did not stop multiple sclerosis entirely. That suggests there are likely other factors at play -- and much more for scientists to explore.

An Important Proof of Principle
UVA's new research offers important insight into the function and role of the lymphatic vessels that connect the brain to the immune system. In most aspects, they work exactly as scientists would expect -- just like other lymphatic vessels in the body.
"Meningeal lymphatic vessels are quite small compared to other lymphatics in the body, and we and others wondered if this might limit the amount and size of cargo they can pass through," Herz said. "During inflammation, they did not change in size or complexity much, but what was really exciting to discover [was that] they allowed whole immune cells to traffic through them, and we found the molecular cues for that."
the lab's recent research also highlights the complexity doctors face when trying to But manipulate the vessels to benefit human health. For example, blocking the vessels had a benefit in the multiple sclerosis model, but the lab has also shown that the vessels' healthy function is vital to staving off Alzheimer's disease and preventing the cognitive decline that comes with age.
That means that it's unlikely that stopping MS could be as simple as blocking the flow inside the vessels. It also suggests that there is probably no one treatment approach that will work for every neurological disorder. But the emerging importance of the vessels offers doctors an exciting new avenue for tackling neurological diseases.
"These findings on the role of brain-draining lymphatic vessels in MS, together with our recent work on their role in Alzheimer's disease, demonstrate that the brain and the immune system are closely interacting. When these interactions go out of control, pathologies emerge," said Kipnis, chairman of UVA's Department of Neuroscience and director of the BIG Center. "The idea that we could target major neurological disorders through therapeutic manipulation of peripheral structures, such as lymphatic vessels, is beyond exciting. Through our collaboration with PureTech Health, we hope to bring these laboratory findings to improve patients' lives one day."
Kipnis recently signed a deal with biopharmaceutical company PureTech Health to explore the potential clinical applications of his discoveries.


CNS lymphatic drainage and neuroinflammation are regulated by meningeal lymphatic vasculature


Neuroinflammatory diseases, such as multiple sclerosis, are characterized by invasion of the brain by autoreactive T cells. The mechanism for how T cells acquire their encephalitogenic phenotype and trigger disease remains, however, unclear. The existence of lymphatic vessels in the meninges indicates a relevant link between the CNS and peripheral immune system, perhaps affecting autoimmunity. Here we demonstrate that meningeal lymphatics fulfil two critical criteria: they assist in the drainage of cerebrospinal fluid components and enable immune cells to enter draining lymph nodes in a CCR7-dependent manner. Unlike other tissues, meningeal lymphatic endothelial cells do not undergo expansion during inflammation, and they express a unique transcriptional signature. Notably, the ablation of meningeal lymphatics diminishes pathology and reduces the inflammatory response of brain-reactive T cells during an animal model of multiple sclerosis. Our findings demonstrate that meningeal lymphatics govern inflammatory processes and immune surveillance of the CNS and pose a valuable target for therapeutic intervention.

Discussion

Here we show that meningeal lymphatic vessels sample macromolecules and immune cells from the CSF and serve as an important conduit for CNS drainage. We also describe structural features of spinal cord meningeal lymphatics. We expand on our understanding of immune-cell trafficking via the meningeal lymphatic vessels to the draining lymph nodes, which is primarily dependent on CCR7. Using a pharmacological method that we adopted to specifically ablate meningeal (or nasal) lymphatic vessels, we demonstrated that the nasal route drains directly into the sCLNs, while the meningeal lymphatic route drains into both the dCLNs and sCLNs. RNAseq analysis of LECs from mouse meninges, diaphragm, and skin revealed that the meningeal lymphatic vessels exhibited a unique transcriptional profile, which, under local inflammatory conditions, might underlie the distinct behavior of meningeal lymphatics. Attenuation of EAE was obtained after surgical and pharmacological blockade of lymphatic function, suggesting that drainage contributed to the activation of encephalitogenic T cells in the lymph nodes. Supporting this notion, reduction of meningeal lymphatic drainage reduced interactions of 2D2 T cells with local antigen-presenting cells. RNA-seq of activated 2D2 T cells isolated from dCLNs showed that T cells from mice lacking lymphatic drainage acquired a different phenotype from that of controls. These findings warrant further research to identify the cellular (and/or molecular) mediators draining from the CNS and driving T cell encephalitogenicity. Meningeal lymphatic vessels are embedded within the dura. This raises an obvious question: how can macromolecules and immune cells drain from the CSF into meningeal lymphatic vessels, given that the arachnoid mater is supposedly impermeable to CSF45? We noticed, however, that certain spots along the meningeal lymphatics could be seen to take up the tracer from the CSF almost immediately after its injection, whereas tracer uptake along remaining parts of the vessels was slower. Subsequent experiments revealed certain spots along the meningeal lymphatics where the vessel structure was more complex and ramified and where extensions were exposed to the CSF. The structure of these lymphatic sprouts is reminiscent of peripheral-tissue lymphatic buttons, which serve as entry gates into the lymphatic vasculature. Further experiments using electron microscopy technique will be necessary to demonstrate that the meningeal lymphatic vessels are physically crossing the arachnoid mater. Previous reports have implicated the cribriform plate as a major player in the passage of immune cells from the CNS to its draining lymph nodes. Furthermore, a recent study has challenged the potential contribution of the meningeal lymphatics in the drainage of CSF into the CLNs6 . Here using live-imaging, our data (supported by others46) clearly demonstrates the uptake by meningeal lymphatics of tracers injected into the CSF. Our observations, however, do not exclude alternative routes as previously suggested. In the present study, we injected exogenous cells into the cisterna magna and also observed cells in the nasal mucosa and associated lymphatics. However, we could not detect any T cells on the nasal side of the cribriform plate under physiological conditions. Moreover, we labeled endogenous meningeal T cells using laser photoconversion but could not detect any labeled cells in the nasal mucosa. It is possible that if photoconversion of meningeal T cells was complete, some crossing of the cribriform plate by meningeal T cells could have been observed. Furthermore, the speed of injection (and, hence, change in intracranial pressure) appears to be a major factor in facilitating crossing of the cribriform plate by CNS immune cells. Our results thus suggest that the cribriform plate in all probability does not represent a major physiological immunerelevant exit route. This structure has been shown, however, to play an important role in the regulation of CSF homeostasis, since its surgical blockade results in an immediate and constant increase in CSF pressure47. Our results also show that chronic neuroinflammation is accompanied by expansion of the lymphatic vasculature localized around the cribriform plate (as opposed to brain and spinal cord meningeal lymphatics), suggesting that the nasal region might have a more important function at later stages of disease development. Several organs (such as lungs48, for example) have been suggested as sites at which CNS-specific T cells become ‘licensed’ to acquire an appropriate migratory profile that will allow them to infiltrate the CNS. Our data suggest that dCLNs could be another site for T cell licensing or reactivation. Dendritic cells migrating from different tissues have been shown to uniquely influence T cell activation and migration49, and MOG-loaded dendritic cells reportedly activate T cells in the CLNs before their migration into the CNS50. In the context of EAE (both induced and spontaneous), excision of the brain-draining lymph nodes has been shown to delay or attenuate disease development38–40. In spontaneous models, limitation of the drainage of MOG into the dCLNs, thereby preventing activation of MOG-specific T cells, is a likely mechanism. A similar scenario might apply when meningeal lymphatics are ablated. It is important to note that meningeal lymphatic ablation only attenuates and ameliorates EAE but does not completely stop it, suggesting that other routes are involved. Although no side effects were found when using the Visudyne approach, future development of targeted techniques will allow researchers to discern the role of anatomically distinct lymphatics in EAE. Overall, the work described here provides the first characterization, to our knowledge, of the meningeal lymphatic system in the context of brain immunity and neuroinflammation and opens the way to a better understanding of brain immune surveillance and the generation of CNS-directed immune responses. These results might help to uncover the etiology of the immune imbalance typical of neuroinflammatory disorders, with promising implications for therapy

  
                           

Dementia including Alzheimer’s

Brain discovery could block aging's terrible toll on the mind

Faulty brain plumbing to blame in Alzheimer's, age-related memory loss -- and can be fixed


Aging vessels connecting the brain and the immune system play critical roles in both Alzheimer's disease and the decline in cognitive ability that comes with time, new research reveals. By improving the function of the lymphatic vessels, scientists have dramatically enhanced aged mice's ability to learn and improved their memories. The work may provide doctors an entirely new path to treat or prevent Alzheimer's disease, age-related memory loss and other diseases. 
Kipnis and his colleagues were able to use a compound to improve the flow of waste from the brain to the lymph nodes in the neck of aged mice. The vessels became larger and drained better, and that had a direct effect on the mice's ability to learn and remember. "Here is the first time that we can actually enhance cognitive ability in an old mouse by targeting this lymphatic vasculature around the brain," Kipnis said. "By itself, it's super, super exciting, but then we said, 'Wait a second, if that's the case, what's happening in Alzheimer's?'"
The researchers determined that obstructing the vessels in mice worsens the accumulation of harmful amyloid plaques in the brain that are associated with Alzheimer's. This may help explain the buildup of such plaques in people, the cause of which is not well understood. "In human Alzheimer's disease, 98 percent of cases are not familial, so it's really a matter of what is affected by aging that gives rise to this disease," said researcher Sandro Da Mesquita, PhD. "As we did in mice, it will be interesting to try and figure out what specific changes are happening in the old [brain] lymphatics in humans so we can develop specific approaches to treat age-related sickness."
Kipnis noted that impairing the vessels in mice had a fascinating consequence: "What was really interesting is that with the worsening pathology, it actually looks very similar to what we see in human samples in terms of all this aggregation of amyloid protein in the brain and meninges," he said. "By impairing lymphatic function, we made the mouse model more similar to human pathology."

Treating -- or Preventing -- Alzheimer's
The researchers now will work to develop a drug to improve the performance of the lymphatic vessels in people. (Kipnis just inked a deal with biopharmaceutical company PureTech Health to explore the potential clinical applications of his discoveries.) Da Mesquita also noted that it would be important to develop a method to determine how well the meningeal lymphatic vasculature is working in people.
The researchers believe that the best way to treat Alzheimer's might be to combine vasculature repair with other approaches. Improving the flow through the meningeal lymphatic vessels might even overcome some of the obstacles that have doomed previously promising treatments, moving them from the trash heap to the clinic, they said.
It may be, though, that the new discovery offers a way to stave off the onset of Alzheimer's to the point that treatments are unnecessary -- to delay it beyond the length of the current human lifespan.
"It may be very difficult to reverse Alzheimer's, but maybe we would be able to maintain a very high functionality of this lymphatic vasculature to delay its onset to a very old age," Kipnis said. "I honestly believe, down the road, we can see real results."


Outflow of cerebrospinal fluid is predominantly through lymphatic vessels and is reduced in aged mice


Cerebrospinal fluid (CSF) has been commonly accepted to drain through arachnoid projections from the subarachnoid space to the dural venous sinuses. However, a lymphatic component to CSF outflow has long been known. Here, we utilize lymphatic-reporter mice and high-resolution stereomicroscopy to characterize the anatomical routes and dynamics of outflow of CSF. After infusion into a lateral ventricle, tracers spread into the paravascular spaces of the pia mater and cortex of the brain. Tracers also rapidly reach lymph nodes using perineural routes through foramina in the skull. Using noninvasive imaging techniques that can quantify the transport of tracers to the blood and lymph nodes, we find that lymphatic vessels are the major outflow pathway for both large and small molecular tracers in mice. A significant decline in CSF lymphatic outflow is found in aged compared to young mice, suggesting that the lymphatic system may represent a target for age-associated neurological conditions 


Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease




Autism

While Kipnis is busy developing a drug to improve the lymphatic drainage from the aging brain, some people believe they can achieve something similar via massage.

I have no idea if this really is possible, but this is the idea being practised on children with autism in Italy.

So, because this is after all an autism blog, let’s see what the Italian have been up to.





In this study we report the results of a protocol for improving brain lymphatic flow in autism through lymphatic drainage massage, a technique successfully used in a variety of conditions where intracranial lymphatic circulation is hampered by obstacles at the level of deep cervical nodes. At the end of May 2018, the Biomedical Centre for Autism Research and Treatment started implementing a protocol of manual lymphatic drainage of the deep cervical nodes on autistic subjects. By October 2018, several scores of patients had been treated with this protocol. In this report, we describe the cases of three autistic patients for whom manual lymphatic massage was remarkably effective. To our knowledge, this is the first report of lymphatic drainage massage at the level of the deep cervical nodes in autism. Symptomatic improvement was robust and we attribute these results to the effects of the massage on the intracranial lymph or sometimes referred to as the glymphatic circulation with improvement of brain lymphatic drainage believed leading to a decrease of neuroinflammation. In addition to stimulating lymphatic drainage, we postulate that the protocol may serve also as vagus nerve stimulation. The protocol also targets the larynx in a manner similar as described for laryngeal manual therapy for the treatment of dysphonia, and this factor may be contributing to the overall improvement of symptoms, with particular reference to speech. Based on the cases described in this report and on our ongoing research, we are convinced that this type of inexpensive, harmless and easy-to-implement approach of manual lymphatic drainage can be beneficial to autistic patients and represents a new and promising treatment. We expect that the described protocol will play a central role in future treatments for autism, both alone and in combination with other therapies such as behavioral therapies or nutritional interventions.

Case Reports

Patient 1:

Male, 2 years and 9 months old at the time of implementing the manual lymphatic drainage protocol. The patients showed first signs of autism at 20 months of age when he lost the few words he had learned, lost eye contact, stopped responding when called, and began bizarre behaviors - motor stereotypies - that included flapping. Subsequently, this patient developed crises of anger and violent tantrums, in particular when contradicted. The patient did not show significant bio-humoral alterations with the exception of slightly elevated platelet count and IgE. The patient had frequent bowel movements with very soft and hypocholic feces. Three days after implementation of the manual lymphatic drainage protocol, the patient spontaneously begun speaking a few words and eating without the need of assistance, properly using the tableware. Bowel movement were reduced to two movements per day with well-formed feces. The patient begun showing curiosity toward new foods and flapping progressively disappeared. In the following two months, he significantly increased the complexity of his vocabulary and the ability to appropriately follow complex instructions. Stereotypies disappeared and ability of learning during behavioral therapies significantly improved.

Patient 2:

Female, 9 years old at the time of implementing the manual lymphatic drainage protocol, with confirmed diagnosis of early-onset autism and recurrent allergic asthma requiring desloratadine treatment. The most prominent autism symptoms were motor stereotypies, speech limited to very simple sentences, and significant delay in learning. Immediately after implementation of the manual lymphatic drainage, a slight, temporary, enlargement of latero-cervical nodes lasting for a few days was noted, possibly due to mobilization of lymph. Evident improvement of autistic symptoms consisted in spontaneous, faster and easier learning at school with increased alertness and focus. Ability in performing coordinated fine movements significantly increased and the patient began to write; this in turn resulted in increased self-esteem. Motor stereotypies significantly decreased and personal autonomy significantly increased.

Patient 3:

Male, 6 years and 6 months old at the time of implementing the manual lymphatic drainage protocol. The patients showed first signs of autism at 15 months of age when he stopped developing speech, lost eye contact, stopped responding when called and refrained from social interactions. A diagnosis of atypical autism with hyperactivity and attention deficit was proposed at the age of 5. The child had chronic allergic rhinitis and sinusitis with persistent nasal congestion that caused open mouth breathing. The patient was very selective in his eating habits and only ate a few types of fried foods. Following implementation of the manual lymphatic drainage protocol, chronic nasal congestion was rapidly resolved, and nose breathing was reestablished. Eating habits were significantly improved and the patient began eating a variety of healthier foods. The patient also showed improvement in socialization; began to look at other children, trying to imitate their actions. Also, significant improvements in speech were observed with the patient speaking more complex sentences with better pronunciation.



Conclusion

I think it is very likely that something in today’s post is indeed very relevant to much autism.

Now we know not to blame only the vagus nerve for transmitting inflammatory signals from the body to the brain.

Hopefully the researchers will eventually pursue their original idea from 2015 that the study of meningeal lymphatics might lead to autism therapies.

We are of course at liberty to learn from the Alzheimer’s and MS research and develop our own therapies.






Thursday, 18 April 2019

Wnt, TCF4 and Pre-myelinating Oligodendrocytes


Cartoons in art class - Monty is getting ready for Easter break, but not in the Maldives

Today’s post may sound very complicated and narrow, but it is very relevant to people with the following: - 

·        Pitt Hopkins Syndrome (insufficient expression of the Transcription Factor #4  TCF4 gene)

·        Multiple Sclerosis

·        Some Mental Retardation/Intellectual Disability (MR/ID)

·        Schizophrenia

·        Impaired Wnt signalling

·        Perhaps PAK1 inhibitor responders

I do feel that Multiple Sclerosis could be treated very much better if some effort was made to translate the existing science, freely available to all, into therapy. You could greatly improve many people’s lives just by repurposing cheap existing drugs.
In simple terms, to produce myelin that you need to coat axons in your brain, you need a type of cell called an oligodendrocyte (OL).  You need a lot of these cells and you need them to get busy. They place tiny pieces of white insulation along axons of your brain cells, this produces the so called “white matter”.  These pieces of insulation are needed to make electrical signals flow correctly in your brain.
It has been shown that in some people the oligodendrocyte precursors (OLPs) do not “mature” and instead get stuck as premyelinated oligodendrocytes (pre-OL). That means reduced myelination and loss of white matter.

It is clearly shown in the graphic below: -








































Tcf4 is expressed in oligodendrocyte lineage in human developmental white matter and in active areas of MS lesions. (A) Tcf4 is expressed in white matter tracts during myelination of human developmental brain at postnatal age 1 mo, 3.5 mo, and 16 mo, but is not expressed by 7 yr. Tcf4 colocalizes with Olig2 when expressed in the developing human corpus callosum. (B) Tcf4 protein expression is evident in active MS lesions, but it is not seen in normal-appearing white matter (NAWM) or in the core of chronic MS lesions. An illustrative MS case is shown with several lesion types present. NAWM stains with Luxol Fast Blue (LFB) and contains sparse LN3(HLA-DR)-positive inflammatory cells, organized SMI-31 axon fibers, and no Tcf4-positive cells. Chronic plaques have sparse LFB staining and LN3-positive cells, intact axons, but no Tcf4-positive cells. In contrast, Tcf4-positive cells are present in active areas of plaques with abundant LN3-positive cells and intact demyelinated axons. Tcf4 expression in active lesions colocalizes (open arrowheads) with a subset of Olig2 cells.


Don’t worry if you don't follow everything. There is nothing wrong with your white matter.
We come back to Wnt signalling that we covered in depth in older posts. This is a complex signalling pathway implicated in autism, some cancers and other conditions. You can both increase and reduce Wnt signalling, which will affect the transcription of numerous genes.
TCF4 is the Pitt Hopkins gene. We have across this syndrome several times, while it is rare, a milder miss-expression of the gene is actually quite common.  Reduced expression of TCF4 is a common feature of MR/ID very broadly. TCF4 has been found to be over-expressed in schizophrenia.
People with Multiple Sclerosis (MS) have been found to have oligodendrocytes “stuck” as non-myelinating (premyelinated oligodendrocytes, pre-OL). Inhibiting the Wnt pathway might play a role in treatment during periods of acute demyelination, when there is a lack of newly minted myelin-producing oligodendrocytes. The study below does refer to Wnt inhibitors in the pipeline as potential cancer therapies.  It looks to me that safe Wnt inhibitors like the cheap drugs widely used to treat children with parasites (Mebendazole/ Niclosamide) could be repurposed to treat the acute phase of multiple sclerosis.
Mebendazole/ Niclosamide are safe and dirt cheap, whereas the (slightly) disease changing MS drugs currently cost $50,000+ a year.

TCF4 links everything together
Wnt signalling needs to be active to block premyelinated oligodendrocytes into transforming into oligodendrocytes (OL). So by inhibiting Wnt signalling you may remove one of the problems in MS; you probably only need to do this during relapses of MS.  
There actually is a finally stage to getting the oligodendrocytes (OL) to myelinate many axons and not be lazy.
In the jargon “dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination”.
A miss-expression of TCF4 is clearly also going to affect myelination and its does in both Pitt Hopkins and MS.
One feature of Pitt Hopkins (caused by haploinsufficiency of the transcription factor 4) is indeed delayed myelination measured via MRI at the age of 1. By the age of 9 white matter (the myelin-coated part of your brain) appears normal. This fits with what I highlighted in red under figure 6 above.
Nothing is simple. Activating Wnt signalling is known to increase expression of TCF4.  


The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that 50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned—but not normal—adult white matter. We report that β-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt–β-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of β-catenin in the oligodendrocyte lineage in vivo and (2) findings from APCMin mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt–β-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders 
Potential Tcf4-catenin activities in oligodendrocyte development
The pattern of Tcf4 protein expression, from P1 to P30 and during remyelination after injury, defines the window of potential canonical Wnt pathway functions. Within this context, we observed that Tcf4 expression marked 15%–20% of OLPs at any given stage assessed. These findings were consistent with two possibilities. First, Tcf4 expression could demarcate a subset of OLPs. Second, it was possible that Tcf4 expression transiently marks all (or the vast majority) of OLPs during development. Our functional evidence strongly supports the latter conclusion, based on the fact that activity of activated β-catenin is Tcf-dependent (van de Wetering et al. 2002), coupled with the robust phenotype in DA-Cat and APCMin animals, in which we observe pervasive effects of Wnt pathway dysregulation on myelin production throughout the CNS. Interestingly, although Tcf4 proteins are coexpressed with nuclear Olig1 proteins, Tcf4 segregated from cells expressing Olig1 mRNA transcripts, consistent with the possibility that Tcf4 is expressed at a transition stage when nuclear Olig1 proteins become down-regulated during remyelination.

Previous work has suggested inhibitory functions of Tcf4 on myelin basic protein gene expression in vitro (He et al. 2007), and our studies indicate that Tcf4 interactions with β-catenin inhibit myelination in vivo. Additional studies are warranted to rule out possible β-catenin-independent roles for Tcf4 in oligodendrocyte development. Although Wnt pathway activation has conventionally been thought of as activating gene targets, recent work has identified novel Tcf–β-catenin DNA regulatory binding sites that repress targets (Blauwwkamp et al. 2008). In this regard, one intriguing candidate target is HYCCIN (DRCTNNB1A), a Wnt-repressed target (Kawasoe et al. 2000) with essential roles in human myelination (Zara et al. 2006), which is expressed in rodent oligodendrocytes and down-regulated in Olig2cre/DA-Cat mice (Supplemental Fig. 8). Further studies are needed to better understand Tcf4–catenin function and its direct gene targets during oligodendrocyte lineage progression.

Wnt pathway dysregulation in OLPs as a mechanism leading to chronic demyelination in human white matter diseases
Therapeutic opportunities might arise from an enhanced understanding of the process regulating normal kinetics of remyelination. How might the negative regulatory role of the canonical Wnt pathway help to explain the pathology of demyelinating disease? Delayed remyelination due to Wnt pathway dysregulation in OLPs could lead to chronic demyelination by OLPs then missing a “critical window” for differentiation (Miller and Mi 2007; Franklin and Ffrench-Constant 2008). This “dysregulation model” of remyelination failure requires the Wnt pathway to be active during acute demyelination, as suggested by data from our animal systems and human MS tissue.
Canonical WNT signaling has been implicated in a variety of human diseases (Nelson and Nusse 2004), and gain-of-function mutations in β-catenin are etiologic in several cancers including the majority of colon adenocarcinomas. Approaches for treating Wnt-dependent cancers by promoting differentiation (and hence cell cycle arrest or apoptosis) using pharmacological inhibitors of the pathway are under development (Barker and Clevers 2005). It is possible that such antagonists might play a role in the therapeutic enhancement of remyelination by normalizing the kinetics of myelin repair. If so, the animal models described here (e.g., APC+/−) should be useful in preclinical testing. However, it is important to note that while dysregulation of a pathway might delay remyelination, it is overly simplistic to expect that inhibition of the same pathway would accelerate repair in the complex milieu of an MS lesion in which several inhibitory pathways might be active, compounded by the presence of myelin debris (Kotter et al. 2006). Indeed, because of the need to synergize with other processes (e.g., those associated with inflammation), accelerated differentiation might negatively affect repair (Franklin and Ffrench-Constant 2008). Further work is needed to comprehensively understand interactions of regulatory networks required for optimal remyelination and how these may be dysregulated in human demyelinating diseases.

Neurologic and ocular phenotype in Pitt-Hopkins syndrome and a zebrafish model.


Abstract


In this study, we performed an in-depth analysis of the neurologic and ophthalmologic phenotype in a patient with Pitt-Hopkins syndrome (PTHS), a disorder characterized by severe mental and motor retardation, carrying a uniallelic TCF4 deletion, and studied a zebrafish model. The PTHS-patient was characterized by high-resolution magnetic resonance imaging (MRI) with diffusion tensor imaging to analyze the brain structurally, spectral-domain optical coherence tomography to visualize the retinal layers, and electroretinography to evaluate retinal function. A zebrafish model was generated by knockdown of tcf4-function by injection of morpholino antisense oligos into zebrafish embryos and the morphant phenotype was characterized for expression of neural differentiation genes neurog1, ascl1b, pax6a, zic1, atoh1a, atoh2b. Data from PTHS-patient and zebrafish morphants were compared. While a cerebral MRI-scan showed markedly delayed myelination and ventriculomegaly in the 1-year-old PTHS-patient, no structural cerebral anomalies including no white matter tract alterations were detected at 9 years of age. Structural ocular examinations showed highly myopic eyes and an increase in ocular length, while retinal layers were normal. Knockdown of tcf4-function in zebrafish embryos resulted in a developmental delay or defects in terminal differentiation of brain and eyes, small eyes with a relative increase in ocular length and an enlargement of the hindbrain ventricle. In summary, tcf4-knockdown in zebrafish embryos does not seem to affect early neural patterning and regionalization of the forebrain, but may be involved in later aspects of neurogenesis and differentiation. We provide evidence for a role of TCF4/E2-2 in ocular growth control in PTHS-patients and the zebrafish model. 


Conclusion  

If you have a myelinating disease, you might want to read up on TCF4 and Wnt signalling. Probably not what the Minions take to read on the beach in the Maldives.

We also should recall the importance of what I am calling the "what, when and where" in neurological disorders. This is important for late onset disorders like schizophrenia, since the symptoms often develops in late teenage years and so it is potentially preventable, if identified early enough.

Today we see that TCF4 is expressed in white matter only in early childhood. If you knew what changes take place in the brains of children who go on to develop schizophrenia, you might well be able to prevent its onset.

Preventing some autism is already possible, as has been shown in mouse models, but in humans it is more complicated because of the "when" and quite literally the "where". There will be a post showing how the brain overgrowth typical of autism can be prevented using bumetanide, before it occurs, at least in mice.