EAE gets explained in many ways and you asked about a report on how researchers find a way to repair nerves.
Is this the right view, because we are about to do a trial that will do the exact opposite?
Well not Quite the opposite. Is the cholesterol pathway opening the door to repair
Well not Quite the opposite. Is the cholesterol pathway opening the door to repair
Itoh N, Itoh Y, Tassoni A, Ren E, Kaito M, Ohno A, Ao Y, Farkhondeh V, Johnsonbaugh H, Burda J, Sofroniew MV, Voskuhl RR.Cell-specific and region-specific transcriptomics in the multiple sclerosis model: Focus on astrocytes. Proc Natl Acad Sci U S A. 2017 Dec 26. pii: 201716032.
Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are complicated by alterations in cellular composition during disease. Multiple sclerosis (MS) is multifocal by definition. Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE). Astrocyte-specific RNAs from various neuroanatomic regions were attained using RiboTag technology. Sequencing and bioinformatics analyses showed that EAE-induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex, and hippocampus. The top gene pathways that were changed in astrocytes from spinal cord during chronic EAE involved decreases in expression of cholesterol synthesis genes while immune pathway gene expression in astrocytes was increased. Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression. The potential role of cholesterol synthesized by astrocytes during EAE and MS is discussed. Together, this provides proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions during multifocal neurological diseases.
Hypothetical effect of reduced cholesterol synthesis in astrocytes during EAE. (A) Peripheral cholesterols cannot enter into the CNS due to the blood–brain barrier; thus, cholesterols in the CNS are synthesized de novo. In adults, astrocytes are the main cells producing cholesterols , with transport via ATP-binding cassette transporter (ABCA1) to apolipoprotein E (ApoE) to neurons to make membranes and synapses, and to oligodendrocytes to make myelin. (B) In EAE, there is synaptic loss, axonal damage, and demyelination. Here, we hypothesize that less cholesterol synthesis in astrocytes during EAE may lead to reduced cholesterol for transport to neurons and oligodendrocytes, thereby reducing reparative synaptic plasticity and remyelination.
It has been said that
"They hypothesized that while inflammation causes loss of myelin and synapses, it is the decrease in cholesterol synthesis gene expression in astrocytes that explains why lesions do not repair in MS. They treated MS mice with a drug that increased expression in cholesterol synthesis genes and this resulted in improved walking ability.
This disability-specific discovery approach represents a strategy for finding neuroprotective treatments for neurodegenerative diseases that are tailored to repair damage for each disability, one at a time, in contrast to a "one size fits all" treatment approach."
I wasn't sure where this one was coming from but having read a piece in medical express.com I see what they are suggesting: "UCLA researchers proposed that molecular mechanisms behind each disability may differ, and that neuroprotective treatments tailored for each disability may be more effective than nonspecific treatments aiming to reduce a composite of different disabilities".
Is this new?
I say "Come on people we have known the molecular mechanism: of bladder dysfunction, of pain sensation, of epilepsy, or walking are different because they respond to different classes of drugs". So the concept is teaching granny to suck eggs (CLICK).
I say "Come on people we have known the molecular mechanism: of bladder dysfunction, of pain sensation, of epilepsy, or walking are different because they respond to different classes of drugs". So the concept is teaching granny to suck eggs (CLICK).
In this study the claim is is its due to astrocytes
In this study they looked at astrocytes in spinal cord the site of most pathology in EAE, The optic nerve (vision) which has a few lesions in EAE depending on strain and antigen used to induce disease, the cerebellum (movement coordination) has no or a few lesions depending on strain and the hippocampus (memory function) that has no lesions depending on strain and lab.
They look for the message in astrocytes and see the most change in the spinal cord and say it is all about regional pathology and symptom control, but if they didn't see a difference, you would be saying this is a rubbish study as this is where the action is in EAE.
Everyone (OK almost everyone) knows the action is in the spinal cord in these animal models. This is EAE, In most animals, brain lesions are less common or don't really (in rodents, less so in non-human primates) occur except occasionally in the cerebellum.
Anyway back to this study...They see a decrease in the cholesterol synthesis pathway in the spinal cord and make the idea that this is what is the problem with repair and increase cholesterol synthesis in EAE and it gets better.
Great let's do this.
Now. is the great result due to increasing repair, increasing synapse? as implied or some other possibly anti-immune effect?
The drug is working to slow disease development (see above) as they all don't get sick at the same time but the drug-treated recover whereas the placebo don't as would be expected if it was all about repair.
So the animal study does not really support the idea of how the authors view it to be working.
A decrease in cholesterol pathway genes in EAE, the spinal cord is hardly new (CLICK).
But are we now doing a trial with statins that block the cholesterol pathway in MS. Is this the wrong thing to do?
However, have there not been umpteen studies in EAE using statins to block EAE and even studies with the addition of squalene to show the effect was upstream of cholesterol (CLICK).
Remember it is nerves that make synapses and oligodendrocytes that make myelin.
However, I am not saying lack of cholesterol synthesis in astrocytes is not important, but I could equally take another paper to say astrocytes are important for other reasons,
Brambilla et al. Astrocytes play a key role in EAE pathophysiology by orchestrating in the CNS the inflammatory response of resident and peripheral immune cells and by suppressing remyelination. Glia. 2014;62(3):452-67.
Likewise, one can argue that the cholesterol pathway is affected in other cell types.
The other pathway changed is antigen presenting genes.
In the early 1980's people wasted a lot of time trying to prove that astrocytes and endothelial cells were antigen presenting cells causing pro-inflammatory events, but when you looked properly there was little evidence that astrocytes actually express MHC class II in vivo (needs to be done by immuno electron microscopy rather than simple immunocytochemistry because it doesn;t have the resolution) so they are not going to be presenting antigen to CD4 T cells...maybe its all CD8's)
Update 19.00. Thanks to "Luis" see Comments
However, what does this CS (above) drug actually do?
During adulthood, astrocytes are the main CNS cells producing cholesterols, with transport via apolipoprotein E (ApoE) to neurons to make membranes and synapses and to oligodendrocytes to make myelin. In this paper they suggested that decreased cholesterol synthesis in astrocytes during EAE could lead to decreased cholesterol transport. Thus, we investigated CS-drug, an agonist for ATP-binding cassette transporter A1 (ABCA1) that is known to increase efflux of cholesterol to extracellular ApoE. So it will not only affect cholesterol efflux from astrocytes it is going to do this macrophages too could this be important.
Thanks to Luis for bringing this new paper to my attention
APOE is transcriptionally activated by the liver X receptor (an important regulator of cholesterol, fatty acid, and glucosehomeostasis) and peroxisome proliferator-activated receptor γ, nuclear receptors that form heterodimers with retinoid X receptors.
These RXR receptors are being targeted by Prof Franklinstein and Coles in Cambridge with a drug called bexarotene, in a phase 2 clinical trial to promote remyelination.
In this current study by stimulation of reverse cholesterol transport it was possible to restore the capacity of old mice to remyelinate lesioned tissue. The cholesterol laden myelin debris can overwhelm the macrophages to create cholesterol crystals and blocks repair. So have they found the elixir of youth?
However, this does all this work mean there is an easy way to promote repair, the paper on astrocytes above gives us one route with an agent that is getting in the brain or is there a simple treatment used in the treatment of type II diabetes which promotes cholesterol efflux from macrophages (CLICK). Will this be of use in oligodendrocyte function, as has been reported (CLICK).
Maybe a common pathway with CoEnzyme 10 influnece on ABC-G1 mediated cholesterol efflux or even blood proteins (CLICK). This also links to mitochondrial function. Maybe clarity is occurring.
The other pathway changed is antigen presenting genes.
In the early 1980's people wasted a lot of time trying to prove that astrocytes and endothelial cells were antigen presenting cells causing pro-inflammatory events, but when you looked properly there was little evidence that astrocytes actually express MHC class II in vivo (needs to be done by immuno electron microscopy rather than simple immunocytochemistry because it doesn;t have the resolution) so they are not going to be presenting antigen to CD4 T cells...maybe its all CD8's)
Update 19.00. Thanks to "Luis" see Comments
However, what does this CS (above) drug actually do?
During adulthood, astrocytes are the main CNS cells producing cholesterols, with transport via apolipoprotein E (ApoE) to neurons to make membranes and synapses and to oligodendrocytes to make myelin. In this paper they suggested that decreased cholesterol synthesis in astrocytes during EAE could lead to decreased cholesterol transport. Thus, we investigated CS-drug, an agonist for ATP-binding cassette transporter A1 (ABCA1) that is known to increase efflux of cholesterol to extracellular ApoE. So it will not only affect cholesterol efflux from astrocytes it is going to do this macrophages too could this be important.
Thanks to Luis for bringing this new paper to my attention
Cantuti-Castelvetri L et al. Defective cholesterol clearance limits remyelination in the aged central nervous system. Science 04 Jan 2018: eaan4183 DOI: 10.1126/science.aan4183
Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation, phagolysosomal membrane rupture, and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters including apolipoprotein E. Remarkably, stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals thereby inducing a maladaptive immune response that impedes tissue regeneration.
In the past Prof Franklinstein and Colleagues have shown us by stitching young and old mice together and giving then only one circulation (young or old) = parabiosis, that old macrophages do not repair as well as young macrophages.
In this new study from Germany they find that the old macrophages accumulate debris and get cholesterol crystals and stimulate the production of inflammasomes. The inflammasome is multiprotein entity consisting of caspase 1, PYCARD, NALP and sometimes caspase 5. The exact composition of an inflammasome depends on the activator which initiates inflammasome assembly, The inflammasome promotes the maturation of the inflammatory cytokines Interleukin 1β (IL-1β) and Interleukin 18 (IL-18). The inflammasome is responsible for activation of inflammatory processes, and has been shown to induce cell pyroptosis, a process of programmed cell death distinct from apoptosis.
Removal of the myelin protein requires cholesteral transporters, one of which is Apolipoprotein E (ApoE). This is a class of proteins involved in the metabolism of fats in the body. It is important in Alzheimer's disease and cardiovascular disease.
Apolipoprotein E is a fat-binding protein (apolipoprotein) that is part of the chylomicron and Intermediate-density lipoprotein (IDLs). These are essential for the normal processing (catabolism) of triglyceride-rich lipoproteins. In peripheral tissues, ApoE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. In the central nervous system, ApoE is mainly produced by astrocytes, and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene family. ApoE is the principal cholesterol carrier in the brain.
Age-associated decline in regeneration capacity limits the restoration of nervous system functionality after injury. In a model for demyelination, we found that old mice fail to resolve the inflammatory response initiated after myelin damage. Aged phagocytes accumulated excessive amounts of myelin debris, which triggered cholesterol crystal formation, phagolysosomal membrane rupture, and stimulated inflammasomes. Myelin debris clearance required cholesterol transporters including apolipoprotein E. Remarkably, stimulation of reverse cholesterol transport was sufficient to restore the capacity of old mice to remyelinate lesioned tissue. Thus, cholesterol-rich myelin debris can overwhelm the efflux capacity of phagocytes, resulting in a phase transition of cholesterol into crystals thereby inducing a maladaptive immune response that impedes tissue regeneration.
In the past Prof Franklinstein and Colleagues have shown us by stitching young and old mice together and giving then only one circulation (young or old) = parabiosis, that old macrophages do not repair as well as young macrophages.
In this new study from Germany they find that the old macrophages accumulate debris and get cholesterol crystals and stimulate the production of inflammasomes. The inflammasome is multiprotein entity consisting of caspase 1, PYCARD, NALP and sometimes caspase 5. The exact composition of an inflammasome depends on the activator which initiates inflammasome assembly, The inflammasome promotes the maturation of the inflammatory cytokines Interleukin 1β (IL-1β) and Interleukin 18 (IL-18). The inflammasome is responsible for activation of inflammatory processes, and has been shown to induce cell pyroptosis, a process of programmed cell death distinct from apoptosis.
Removal of the myelin protein requires cholesteral transporters, one of which is Apolipoprotein E (ApoE). This is a class of proteins involved in the metabolism of fats in the body. It is important in Alzheimer's disease and cardiovascular disease.
Apolipoprotein E is a fat-binding protein (apolipoprotein) that is part of the chylomicron and Intermediate-density lipoprotein (IDLs). These are essential for the normal processing (catabolism) of triglyceride-rich lipoproteins. In peripheral tissues, ApoE is primarily produced by the liver and macrophages, and mediates cholesterol metabolism. In the central nervous system, ApoE is mainly produced by astrocytes, and transports cholesterol to neurons via ApoE receptors, which are members of the low density lipoprotein receptor gene family. ApoE is the principal cholesterol carrier in the brain.
APOE is transcriptionally activated by the liver X receptor (an important regulator of cholesterol, fatty acid, and glucosehomeostasis) and peroxisome proliferator-activated receptor γ, nuclear receptors that form heterodimers with retinoid X receptors.
These RXR receptors are being targeted by Prof Franklinstein and Coles in Cambridge with a drug called bexarotene, in a phase 2 clinical trial to promote remyelination.
In this current study by stimulation of reverse cholesterol transport it was possible to restore the capacity of old mice to remyelinate lesioned tissue. The cholesterol laden myelin debris can overwhelm the macrophages to create cholesterol crystals and blocks repair. So have they found the elixir of youth?
So if you inhibit limiting cholesterol may be useful for facilitating repair.
Does this process explain both grey and white matter lesions?
Grey matter lesions appear to remyelinate well with age but they microglia/macrophages are not being overloaded with lipid as occurs in white matter lesions.
Does this process explain both grey and white matter lesions?
Grey matter lesions appear to remyelinate well with age but they microglia/macrophages are not being overloaded with lipid as occurs in white matter lesions.
The group suggest that there is a subset of oligodendrocytes that may be important.
BCAS1+ (breast carcinoma amplified sequence) oligodendrocytes are restricted to the foetal and early postnatal human white matter but remain in the cortical gray matter until old age. BCAS1+ oligodendrocytes are reformed after experimental demyelination and found in a proportion of chronic white matter lesions of patients with multiple sclerosis (MS) even in a subset of patients with advanced disease.
Fard et al. BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions.Sci Transl Med. 2017 Dec 6;9(419). pii: eaam7816. doi: 10.1126/scitranslmed.aam7816.
BCAS1+ (breast carcinoma amplified sequence) oligodendrocytes are restricted to the foetal and early postnatal human white matter but remain in the cortical gray matter until old age. BCAS1+ oligodendrocytes are reformed after experimental demyelination and found in a proportion of chronic white matter lesions of patients with multiple sclerosis (MS) even in a subset of patients with advanced disease.
Fard et al. BCAS1 expression defines a population of early myelinating oligodendrocytes in multiple sclerosis lesions.Sci Transl Med. 2017 Dec 6;9(419). pii: eaam7816. doi: 10.1126/scitranslmed.aam7816.
Maybe a common pathway with CoEnzyme 10 influnece on ABC-G1 mediated cholesterol efflux or even blood proteins (CLICK). This also links to mitochondrial function. Maybe clarity is occurring.