Breakdown Of Myelin Sheath Research Articles

Lethal adulthood myelin breakdown by oligodendrocyte-specific Ddx54 knockout

Multiple sclerosis (MS) is a leading disease that causes disability in young adults. We have previously shown that a DEAD-box RNA helicase Ddx54 binds to mRNA and protein isoforms of myelin basic protein (MBP) and that Ddx54 siRNA blocking abrogates oligodendrocyte migration and myelination. Herein, we show that MBP-driven Ddx54 knockout mice (Ddx54 fl/fl;MBP-Cre), after the completion of normal postnatal myelination, gradually develop abnormalities in behavioral profiles and learning ability, inner myelin sheath breakdown, loss of myelinated axons, apoptosis of oligodendrocytes, astrocyte and microglia activation, and they die within 7months but show minimal peripheral immune cell infiltration. Myelin in Ddx54fl/fl;MBP-Cre is highly vulnerable to the neurotoxicant cuprizone and Ddx54 knockdown greatly impairs myelination invitro. Ddx54 expression in oligodendrocyte-lineage cells decreased in corpus callosum of MS patients. Our results demonstrate that Ddx54 is indispensable for myelin homeostasis, and they provide a demyelinating disease model based on intrinsic disintegration of adult myelin.

Disease-Associated Oligodendrocyte: New Player in Alzheimer's Disease and CNS Pathologies.

Considerable evidence has shown that the breakdown of myelin has been linked to Alzheimer's disease (AD). Considering the vulnerability of oligodendrocytes to Alzheimer's disease, the myelin sheath breakdown and degeneration are easily induced, suggesting that dysfunction of the oligodendrocytes could be the first step in the progression at the early AD before the occurrence of amyloid and tau pathology. It is considered that amyloid β-peptide (Aβ)-mediated oligodendrocyte dysfunction and demyelination could be manifested through neuroinflammation, oxidative stress, and neuronal ferroptosis. With the development of single-cell sequencing technology, an oligodendrocyte state that increased in association with central nervous system brain pathology (designated as disease-associated oligodendrocytes) has been identified. In the current review, we examine the possible roles of oligodendrocytes in cognitive decline and their molecular characteristics in AD. Altogether, our findings elucidate that targeting oligodendrocytes may be a novel treatment or prevention option for AD.

Awareness Creation of Neurotoxins‐induced Wallerian‐type degeneration causing brain Acetylcholine‐imbalance and frank Alzheimer disease

AbstractBackgroundPresence Environmentally Mediated Intellectual Decline Neurotoxins ('presence‐EMIDN') threats from 'bounded', 'unbounded' and 'pervasive' sources puts everyone at risk of developing neurodegenerative diseases (eg. Alzheimer) once specific lipophilic‐neurotoxins breach the blood‐brain and nose‐brain barriers to reach the brain and build up to harmful thresholds. Such neurotoxins exist; how they provoke Wallerian‐type degeneration to cause FAD have been threaded together from experimental evidenced‐based reviews. My intent/interest is to create awareness and establish the aetiology for FAD, which has remained idiopathic since 1906, when the German Neurologist, Alois Alzheimer, discovered the disease.MethodThrough threaded literature reviews from multiple sourcesResultsMany neurotoxins produce Wallerian‐type degeneration: organophosphorus compounds (DFP, TOCP), acrylamide, n‐hexane and some of its metabolites. Wallerian‐type degeneration have been demonstrated in animals: hens, cats, rats, rabbits. Changes during Wallerian‐type degeneration can be grouped into two (Histopathological and Biochemical): it describes the cascade of events taking place in the distal part of an axon that has been cut or crushed. The histopathological changes occur in stages in the following order of succession: stage a: primary degeneration of axon followed by secondary degeneration of myelin in these order: axon swelling; axon disintegration; loss of normal myelin structures with swelling; tumefaction; and breakdown of myelin sheaths; followed by stage b: Cellular proliferation; and then stage c: Fibrosis. The biochemical changes result from liberations of normal biochemical constituents of axon and myelin. There is specifically a decrease in the CNS neurotransmitter's Acetylcholine content, in stage a (causing deficiency‐imbalance), increase in collagen in stage c, and other stage b changes.ConclusionThere are evidences showing that symptoms of FAD is due to 'Acetylcholine deficiency‐imbalance in the brain' where it exercises Excitatory and Inhibitory effects which progressively kick‐starts FAD with fatalities after 5 years. Establishing this aetiology brings vistas of new hope/challenges for possible therapeutic interventions developments.

Reduction in MLKL-mediated endosomal trafficking enhances the TRAIL-DR4/5 signal to increase cancer cell death

Mixed lineage kinase domain-like (MLKL) is an essential molecule of necroptosis, a cell death process that is initiated by direct disruption of the plasma membrane. During necroptosis, MLKL is phosphorylated by receptor interacting protein kinase-3 (RIPK3 or RIP3), and then translocates to the plasma membrane to disrupt membrane integrity. Recent data suggest that MLKL also has a RIP3-indendent function in the generation of intraluminal and extracellular vesicles (EVs), as well as in myelin sheath breakdown when promoting sciatic nerve regeneration. Here we show that depletion of MLKL enhances TRAIL-induced cell death in a RIP3-independent manner. Depletion of MLKL leads to prolonged cytotoxic signals that increase TRAIL-induced cell death. Initially, TRAIL binds to DR5 at the cell surface and is endocytosed at similar rates in MLKL-expressing and MLKL-depleted cells, eventual degradation of intracellular TRAIL by the lysosome is delayed in MLKL-depleted cells, corresponding with prolonged/enhanced intracellular signals such as p-ERK and p-p38 in these cells. Colocalization of TRAIL with the marker of early endosomes, EEA1 suggests that TRAIL is accumulated in early endosomes in MLKL-depleted cells compared to MLKL-expressing cells. This indicates that depletion of MLKL reduces receptor-ligand endosomal trafficking leading to increased TRAIL-cytotoxicity. An MLKL mutant that compromises its necroptotic function and its function in the generation of EVs was sufficient to rescue MLKL deficiency, suggesting that the N-terminal structural elements necessary for these functions are not required for the function of MLKL in the intracellular trafficking associated with regulating death receptor cytotoxicity. A reduction in MLKL expression in cancer cells would therefore be expected to result in enhanced TRAIL-induced therapeutic efficacy.

Abstract WP142: 18 F-THK5351 PET Imaging of Wallerian Degeneration of the Pyramidal Tract in a Post-Stroke Patient: A Longitudinal Case Study

Introduction: The PET radioligand, 18 F-THK5351, was initially developed to target tau aggregation present in neurofibrillary tangles. However, 18 F-THK5351 was recently reported to bind to monoamine oxidase B (MAO-B) with a certain level of affinity. MAO-B is highly concentrated in astrocytes. MAO-B concentration increases during so-called "gliosis", which is a spectrum of changes in astrocytes that occur after brain injury. Wallerian degeneration of the pyramidal tract usually develops after a cerebral infarction including primary motor cortex. In the early stage, axonal swelling and breakdown of myelin sheath occur. In the later stage, the degenerated axons are replaced by gliosis, which is primarily the proliferation of astrocytes to form a scar. These suggest that 18 F-THK5351 concentrates in the lesion where gliosis occurs in the process of Wallerian degeneration. We now present a case showing a potential use of 18 F-THK5351 PET to identify Wallerian degeneration of the pyramidal tract after a cerebral infarction. Methods: A patient developed left-sided hemiplegia caused by a right middle cerebral artery infarction at the age of 39, and underwent 18 F-THK5351 PET at ages 41 and 42. Emission data were acquired for 20 min starting at 40 min after an intravenous injection of 18 F-THK5351. Images were normalized using the cerebellum as a reference region Results: 18 F-THK5351 images at ages 41 and 42 showed intense uptake along the ipsilateral pyramidal tract from the corona radiata to the medulla (Figure 1, arrows). 18 F-THK5351 uptake slightly decreased at the age of 42. Conclusion: 18 F-THK5351 PET can identify Wallerian degeneration of the pyramidal tract accompanied with gliosis by targeting MAO-B located. This case suggests that gliosis in the process of Wallerian degeneration of the pyramidal tract still remains even three years after the stroke. Figure1: MRI (A) and 18 F-THK5351 images superimposed on MRI at ages 41 (B) and 42 (C)

Mixed Lineage Kinase Domain-like Protein MLKL Breaks Down Myelin following Nerve Injury

Successful regeneration of severed peripheral nerves requires the breakdown and subsequent clearance ofmyelin, tightly packed membrane sheaths of Schwann cells that protect nerve fibers and harbor nerve growth-inhibitory proteins. How Schwann cells initiate myelin breakdown in response to injury is still largely unknown. Here we report that, following sciatic nerve injury, MLKL, a pseudokinase known to rupture cell membranes during necroptotic cell death, is induced and targets the myelin sheath membrane of Schwann cells to promote myelin breakdown. The function of MLKL in disrupting myelin sheaths requires injury-induced phosphorylation of serine 441, an activation signal distinct from the necroptosis-inducing phosphorylation by RIP3 kinase. Mice with Mlkl specifically knocked out in Schwann cells showed delayed myelin sheath breakdown. Lack of MLKL reduced nerve regeneration following injury, whereas overexpression of MLKL accelerated myelin breakdown and promoted the regeneration of axons.

90 - PALB2 Synergizes with ATG7 to Suppress Neurodegeneration

Autophagy is an intracellular self-digestion process that plays a critical role in maintaining neuronal homeostasis. PALB2 is a tumor suppressor protein essential for homologous recombination-based DNA repair, redox homeostasis and breast cancer suppression. We previously showed that deletion of Palb2 in the mouse mammary gland using Cre recombinase driven by the whey acid protein promoter (Wap-cre) led to mammary tumor development, which was delayed in a low-autophagy background. To further understand the role of autophagy in breast cancer development, we co-deleted the essential autophagy gene Atg7 together with Palb2 using Wap-cre. Surprisingly, Wap-cre-driven deletion of Atg7 resulted in neurodegeneration evidenced by motor deficits, and combined deletion of Palb2 and Atg7 led to a similar but much more severe phenotype so that the mice died before mammary tumor development. This was found to be due to a high level of 'leaky' expression of Wap-cre in the brain. Morphologic and immunohistochemical studies revealed that Atg7 deletion caused aberrant accumulation of p62, loss of Purkinje cell in the cerebellum, and progressive formation of inclusion bodies in neurons, Co-deletion of Palb2 with Atg7 significantly accelerated the Purkinje cell loss and inclusion body formation, and increased amount of apoptotic cells and necrotic cells. Electron microscopy further revealed a breakdown of myelin sheath and deformed synapse in Palb2f/f;Atg7f/f; Wap-cre mice. Mechanistically, we found markedly higher levels of DNA damage marker γH2AX and DNA oxidation marker 8-oxo-dG in both Palb2 single and Palb2/Atg7 double deletion brains compared with Atg7 single deletion brain. Taken together, these findings suggest that PALB2 plays an important role in neurons by preventing DNA damage and oxidative stress, and autophagy is required for the normal functioning and survival of neurons in the face of DNA damage and oxidative stress elicited by the loss of PALB2.

P53-Mediated oligodendrocyte apoptosis initiates demyelination after compressed spinal cord injury by enhancing ER-mitochondria interaction and E2F1 expression

Oligodendrocyte apoptosis mediated demyelination is a pathological change characteristic of compressed spinal cord injury (CSCI). However, the mechanism of demyelination due to oligodendrocyte apoptosis is not known. In this study, after successfully establishing a rat CSCI model using a custom-made compressor, we investigated the pathological changes, MBP expression, as well as apoptosis-related protein (p53, active caspase-3) expression to determine whether or not apoptosis and demyelination occurred after injury. To understand the possible mechanism of oligodendrocyte apoptosis, caspase-12 and cytochrome C were analyzed to explore the relationship between oligodendrocyte apoptosis and endoplasmic reticulum(ER)-mitochondria interaction. The transcription factor, E2F1, was also detected by immunofluorescence and Western blot assays. The results showed that CSCI increased the expression levels of p53, E2F1 and active caspase-3 followed by the swelling and breakdown of myelin sheaths. The number of myelinated nerve fibers also decreased with down-regulated expression of MBP. Expression levels of caspase-12 and cytochrome C were enhanced along with a reduction in the number of oligodendrocytes. After treatment of CSCI in rats with Pifithrin-μ(PFT-μ), a specific inhibitor of p53, pathomorphological changes of myelin sheath improved significantly. Expression levels of E2F1, active caspase-3, caspase-12 and cytochrome C were down-regulated, consistent with reduced the number of apoptotic oligodendrocytes. These results demonstrated that over-expression of p53 could mediate oligodendrocyte apoptosis thus resulting in demyelination in two ways; by enhancing ER-mitochondria interaction and by triggering the E2F1 mediated apoptosis pathway.

Loss of Myelin Basic Protein Function Triggers Myelin Breakdown in Models of Demyelinating Diseases.

SummaryBreakdown of myelin sheaths is a pathological hallmark of several autoimmune diseases of the nervous system. We employed autoantibody-mediated animal models of demyelinating diseases, including a rat model of neuromyelitis optica (NMO), to target myelin and found that myelin lamellae are broken down into vesicular structures at the innermost region of the myelin sheath. We demonstrated that myelin basic proteins (MBP), which form a polymer in between the myelin membrane layers, are targeted in these models. Elevation of intracellular Ca2+ levels resulted in MBP network disassembly and myelin vesiculation. We propose that the aberrant phase transition of MBP molecules from their cohesive to soluble and non-adhesive state is a mechanism triggering myelin breakdown in NMO and possibly in other demyelinating diseases.

The Clinical Features and Diagnosis of Adrenoleukodystrophy: A Case Series of Iranian Family.

Adrenoleukodystrophy disorder is one of the x-linked genetic disorders caused by the myelin sheath breakdown in the brain. In this study, we present 4 yr experience on this disorder. The patients diagnosed as adrenoleukodystrophy in the Neurology Department of Mofid Children's Hospital in Tehran, Iran from 2010 to 2014 were enrolled into the study. The disorder was confirmed by neuroimaging and clinical findings along with genetic and neurometabolic assessment at Reference Laboratory in Germany. We assessed age, gender, past medical history, developmental status, clinical manifestations, and neuroimaging findings of populous family with adrenoleukodystrophy. All of the patients were one populous family with high rate of consanguineous marriages. This disorder was confirmed by genetic assessment, VLCFA and brain MRI. c.253_254insC, p.R85Pfs112* was found in heterozygote state and the VLCFA assessment showed the typical pattern for adrenoleukodystrophy/ adrenomyeloneuropathy. This diagnosis was in agreement with the family history and the clinical history of the patient. Since there have been a number of cases in patient's family in the past, so intensive follow-up on the family especially detection the female members of the family of childbearing age was recommended. The amount of C-26, C24/C22 and C26/C22 was elevated. All patients with the same genotype had wide ranges of clinical presentation. Early diagnose of this disease might help us for early intervention and prenatal diagnosis for the disease in next siblings.

Proteomic Profiling in the Brain of CLN1 Disease Model Reveals Affected Functional Modules.

Neuronal ceroid lipofuscinoses (NCL) are the most commonly inherited progressive encephalopathies of childhood. Pathologically, they are characterized by endolysosomal storage with different ultrastructural features and biochemical compositions. The molecular mechanisms causing progressive neurodegeneration and common molecular pathways linking expression of different NCL genes are largely unknown. We analyzed proteome alterations in the brains of a mouse model of human infantile CLN1 disease-palmitoyl-protein thioesterase 1 (Ppt1) gene knockout and its wild-type age-matched counterpart at different stages: pre-symptomatic, symptomatic and advanced. For this purpose, we utilized a combination of laser capture microdissection-based quantitative liquid chromatography tandem mass spectrometry (MS) and matrix-assisted laser desorption/ionization time-of-flight MS imaging to quantify/visualize the changes in protein expression in disease-affected brain thalamus and cerebral cortex tissue slices, respectively. Proteomic profiling of the pre-symptomatic stage thalamus revealed alterations mostly in metabolic processes and inhibition of various neuronal functions, i.e., neuritogenesis. Down-regulation in dynamics associated with growth of plasma projections and cellular protrusions was further corroborated by findings from RNA sequencing of CLN1 patients' fibroblasts. Changes detected at the symptomatic stage included: mitochondrial functions, synaptic vesicle transport, myelin proteome and signaling cascades, such as RhoA signaling. Considerable dysregulation of processes related to mitochondrial cell death, RhoA/Huntington's disease signaling and myelin sheath breakdown were observed at the advanced stage of the disease. The identified changes in protein levels were further substantiated by bioinformatics and network approaches, immunohistochemistry on brain tissues and literature knowledge, thus identifying various functional modules affected in the CLN1 childhood encephalopathy.

Neuropathology in Mice Expressing Mouse Alpha-Synuclein

α-Synuclein (αSN) in human is tightly linked both neuropathologically and genetically to Parkinson's disease (PD) and related disorders. Disease-causing properties in vivo of the wildtype mouse ortholog (mαSN), which carries a threonine at position 53 like the A53T human mutant version that is genetically linked to PD, were never reported. To this end we generated mouse lines that express mαSN in central neurons at levels reaching up to six-fold compared to endogenous mαSN. Unlike transgenic mice expressing human wildtype or mutant forms of αSN, these mαSN transgenic mice showed pronounced ubiquitin immunopathology in spinal cord and brainstem. Isoelectric separation of mαSN species revealed multiple isoforms including two Ser129-phosphorylated species in the most severely affected brain regions. Neuronal Ser129-phosphorylated αSN occured in granular and small fibrillar aggregates and pathological staining patterns in neurites occasionally revealed a striking ladder of small alternating segments staining either for Ser129-phosphorylated αSN or ubiquitin but not both. Axonal degeneration in long white matter tracts of the spinal cord, with breakdown of myelin sheaths and degeneration of neuromuscular junctions with loss of integrity of the presynaptic neurofilament network in mαSN transgenic mice, was similar to what we have reported for mice expressing human αSN wildtype or mutant forms. In hippocampal neurons, the mαSN protein accumulated and was phosphorylated but these neurons showed no ubiquitin immunopathology. In contrast to the early-onset motor abnormalities and muscle weakness observed in mice expressing human αSN, mαSN transgenic mice displayed only end-stage phenotypic alterations that manifested alongside with neuropathology. Altogether these findings show that increased levels of wildtype mαSN does not induce early-onset behavior changes, but drives end-stage pathophysiological changes in murine neurons that are strikingly similar to those evoked by expression of human wildtype or mutant forms.

Chapter 36 Structural changes in the normally aging cerebral cortex of primates

During normal aging humans exhibit some cognitive decline, but it is difficult to determine the underlying causes of this decline, because information about cognitive status is rarely available and preservation of the brain is usually inadequate for detailed cytological examination. One solution to this problem is to use a nonhuman primate model, such as the rhesus monkey, which exhibits age-related cognitive decline similar to humans, and can be cognitively tested before the brains are preserved for detailed examination. It is now known that cognitive decline in human and nonhuman primates is not due to loss of cortical neurons and there is no correlation between the frequency of senile plaques and cognitive status. Indeed apart from layer 1, neurons of cerebral cortex show few signs of aging, although there may be some loss of synapses throughout cortex. In contrast, both microglia and astrocytes come to contain phagocytosed material, but its origin is unknown. There is also loss of white matter, which is accompanied by some breakdown of myelin sheaths and alterations in oligodendrocytes. It is suggested that the myelin changes alter conduction velocities along axons. This would alter timing in neuronal circuits, contributing to cognitive decline.

Erratum to "Watery and dark axons in Wallerian degeneration of the opossum's optic nerve: different patterns of cytoskeletal breakdown?" [An Acad Bras Cienc 73(2001): 231-243

−→ Fig. 1 – Ultrathin sections of opossum’s optic nerve fibers, 24 (A and B) and 48 hours (C and D) after crush. A. Normal fibers (n) are seen among some altered fibers, which exhibit watery degeneration (star) and myelin sheath breakdown (thick arrow). Note demyelinated fibers (thin arrows) with an apparently intact axoplasmic cytoskeleton. Asterisk, astrocytic processes. Bar = 1.7μm. B. Normal looking optic nerve fiber (n) is seen above an optic fiber showing dark degeneration (star). Bar = 0.4μm. C. Longitudinal section of optic nerve fibers showing areas of focal degeneration of the axoplasmic cytoskeleton (star). Asterisk, astrocytic processes; m, mitochondrial profile. Bar = 0.6μm. D. Observe optic nerve fibers with an apparently normal appearance (n). Among them, there is a fiber with dense axoplasm and some altered organelles, typical of dark degeneration (d). Asterisks, astrocytic processes. Bar = 0.6μm.

Nutritional Depletion Polyneuropathy and Valproic Acid

Nutritional depletion polyneuropathy is a common disorder in our society. Several groups are affected, namely, the poorly nourished, the elderly, the homeless, alcoholics, and recent third-world immigrants. Through several mechanisms, both motor and sensory peripheral nerve tracks are involved. Clinically, most important to the patient are the nociceptive tracks carrying the pain fibers. Thiamine is a necessary coenzyme in the degradation of pyruvic acid to lactic acid. Its deficiency leads to accumulation of pyruvic acid, a known neurotoxin that causes both myelin sheath breakdown and axonal degeneration. 1 Thiamine is also necessary for the production of acetylcholine whose lack further accentuates the breakdown of the neuron. Among affected individuals, pathologic features of the nerve reveal a distal axonopathy, resulting in a dying back of the nerves affected. 2 Once several bundles are involved, erratic impulses are generated and propagated up the spinothalamic tracks and perceived in the thalamus and cortex

Oligodendrocytes and oligodendrocyte/type-2 astrocyte progenitor cells of adult rats are specifically susceptible to the lytic effects of complement in absence of antibody.

The central nervous system of individuals with multiple sclerosis contains lesions specifically characterized by breakdown of myelin sheaths associated with a general failure of repair of demyelinating damage. The cause of myelin breakdown is unknown. Although immune mechanisms have been implicated in this breakdown, no convincing demonstrations of specific immune reaction against myelin have yet been provided in multiple sclerosis patients. Similarly, the cellular biological mechanisms which underlie the failure of myelin repair are unknown. We have found that (i) oligodendrocytes, the cells that produce myelin sheaths in the central nervous system, and (ii) oligodendrocyte/type-2 astrocyte (O/2A) progenitor cells derived from optic nerves of adult rats bind and activate complement in the absence of antibody in vitro, leading to destruction of these cells. Susceptibility to antibody-independent lysis by complement was a cell-type-specific trait of oligodendrocytes and adult O/2A progenitors and was not shared by perinatal O/2A progenitors, type-2 astrocytes, type-1 astrocytes, meningeal cells, or Schwann cells. We suggest that the susceptibility of oligodendrocytes and adult O/2A progenitor cells to complement-induced lysis, combined with other specific properties of adult O/2A progenitors, are consistent with--and may be a contributing factor--both in the generation of demyelinating lesions in multiple sclerosis and also in the failure of these lesions to be successfully repaired in adult multiple sclerosis patients.

Degeneration in the cochlear nerve of the rat following cochlear lesions

Left unilateral cochlear lesions were performed on 26 albino rats at 1.5 months of age. After survival times ranging from 1 h to 6 months, the animals were perfused via the aorta with mixed aldehydes. Blocks including the cochlear nerves were removed, embedded in Araldite, sectioned in a plane transverse to the longitudinal axis of the nerve, and analyzed in the light microscope. Degenerating fiber profiles were grouped into 4 categories, and their relative frequencies were counted, as were numbers of normal fibers and glial cell nuclei. The cross-sectional areas of the nerves were measured. Lesion extent was evaluated by means of sections through operated cochleas from short and long survival times, and right cochlear nerves from 11 of the animals were used as controls. In the left nerves, segmental swelling of fibers occurred as early as 16 h survival, followed by collapse of fibers and breakdown of myelin sheaths. Starting at 36 h survival, increased numbers of glial cells were seen in the nerve. At longer survival times there were decreases in the cross-sectional area of the nerve and in the packing density of degenrating fiber profiles. At the longest survival times, a substantial amount of debris remained which resembled that seen in early stages. Finally, there was evidence of continued loss of nerve fibers occurring over a period of weeks to months.

Remodelling of internodes in regenerated rat sciatic nerve: electron microscopic observations.

Twelve adult rats received a crush lesion of the left sciatic nerve in the upper thigh. Following survival times of 2 weeks to 6 months, the animals were perfused with glutaraldehyde. Longitudinal thin sections from regenerated nerve segments were examined by electron microscopy. At survival periods of 2 weeks to 1 month, exceptionally short internodes composed of a Schwann cell lacking myelin, a more or less wrinkled Schwann cell-myelin sheath unit, or Schwann cell cytoplasm containing lamellated bodies and lipid droplets, were found intercalated between conventional regenerated myelin sheaths. Such intercalated sheaths were always bordered by sites with a nodal differentiation. Although much less frequent, short distorted myelin sheaths were also found at regeneration times of 2 and 3 months, but they have not been found in sections from 6-month specimens. In the long-term regenerated nerves many paranodes were distorted by prominent myelin folds and some nodes of Ranvier exhibited abnormal axon-Schwann cell networks and adaxonal Schwann cell protrusions. These observations show that internodes in regenerated rat sciatic nerves are subject to extensive remodelling. This includes internodal shortening and nodal migration, myelin sheath breakdown and demyelination, elimination of redundant Schwann cells and nodal fusion. These morphological changes may have important physiological implications.

Observations on Wallerian degeneration in explant cultures of cat sciatic nerve.

Wallerian degeneration was studied in vitro using explant cultures of cat sciatic nerve. As these cultures contain no macrophages they highlight the responses of Schwann cells to myelin sheath breakdown. Although there were regional variations in the changes observed in these cultures with respect to time, the sequence of events which lead to Schwann cell proliferation and to fragmentation and liberation of myelin debris into the endoneurial space was established. The initial event was rejection of myelin sheaths by Schwann cells. Liberated Schwann cells then proliferated within the basal lamina tube. In nerve fibres containing proliferating Schwann cells, myelin debris passed through breaks in the basal lamina tube into the endoneurial space. Schwann cells also escaped from the basal lamina tube with the myelin debris. Following the loss of the luminal contents the basal lamina tube collapsed and the intratubular Schwann cells formed bands of Büngner. The Schwann cells which migrated into the endoneurial space and subsequently onto the culture dish retained contact with each other. These studies indicate that rejection of myelin internodes by their supporting Schwann cells set in train a series of events in which Schwann cells and degenerating myelin behaved as separate components. Schwann cells were not involved in phagocytosis or degeneration of myelin. We conclude that Schwann cell proliferation in Wallerian degeneration is directed towards re-establishing cellular continuity within the basal lamina tube which is lost when Schwann cells reject their myelin sheaths.

Immunocytochemical study of myelin-associated glycoprotein (MAG), basic protein (BP), and glial fibrillary acidic protein (GFAP) in chronic relapsing experimental allergic encephalomyelitis (EAE).

Chronic relapsing experimental allergic encephalomyelitis (EAE) lesions that resemble those seen in multiple sclerosis (MS) were produced in young Hartley and strain 13 guinea pigs (Lassmann and Wisniewski 1979). To study distributions of myelin-associated glycoprotein (MAG), myelin basic protein (MBP), and glial fibrillary acidic protein (GFAP) in these lesions, paraffin and semithin epon sections of CNS from eight of these guinea pigs were immuno-stained with antisera to these proteins according to the peroxidase-antiperoxidase (PAP) method. In lesions with active myelin sheath breakdown, changes in anti-MAG and anti-BP immunoreactivity corresponded closely. Abnormal and/or decreased anti-MAG staining did not extend beyond margins of lesions into surrounding areas containing myelin sheaths stained normally by anti-BP and by histological stains for myelin. GFAP-stained astrocyte processes were more numerous and much larger in more chronic lesions. Anti-MAG and anti-BP both stained regenerating myelin sheaths which were very numerous in both paraffin and epon sections. In the latter, anti-MAG also stained some myelin-forming oligodendroglia. The results are additional evidence suggesting that in chronic relapsing EAE, myelin sheaths are the primary target. Oligodendroglia appear to be relatively unaffected and remyelinate most of the demyelinated axons.