In this report, we have investigated the signaling pathways that are activated by, and mediate the effects of, the neuregulins and axonal contact in Schwann cells. Phosphatidylinositol 3-kinase (PI 3-kinase) and mitogen-activated protein kinase kinase (MAPK kinase) are strongly activated in Schwann cells by glial growth factor (GGF), a soluble neuregulin, and by contact with neurite membranes; both kinase activities are also detected in Schwann cell-DRG neuron cocultures. Inhibition of the PI 3-kinase, but not the MAP kinase, pathway reversibly inhibited Schwann cell proliferation induced by GGF and neurites. Cultured Schwann cells undergo apoptosis after serum deprivation and can be rescued by GGF or contact with neurites; these survival effects were also blocked by inhibition of PI 3-kinase. Finally, we have examined the role of these signaling pathways in Schwann cell differentiation in cocultures. At early stages of coculture, inhibition of PI 3-kinase, but not MAPK kinase, blocked Schwann cell elongation and subsequent myelination but did not affect laminin deposition. Later, after Schwann cells established a one-to-one relationship with axons, inhibition of PI 3-kinase did not block myelin formation, but the myelin sheaths that formed were shorter, and the rate of myelin protein accumulation was markedly decreased. PI 3-kinase inhibition had no observable effect on the maintenance of myelin sheaths in mature myelinated cocultures. These results indicate that activation of PI 3-kinase by axonal factors, including the neuregulins, promotes Schwann cell proliferation and survival and implicate PI 3-kinase in the early events of myelination.

https://www.jneurosci.org/content/jneuro/20/12/4635.full.pdf

Axonal Regulation of Schwann Cell Proliferation and Survival and the Initial Events of Myelination Requires PI 3-Kinase Activity

Enzymatic microdetermination of serum free fatty acids

There is a broad consensus that multiple sclerosis (MS) represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, that is, damage to axons, synapses and nerve cell bodies. While we are equipped with appropriate therapeutic options to prevent immune-cell driven relapses, effective therapeutic options to prevent the progressing neurodegeneration are still missing. In this review article, we will discuss to what extent pathology of the progressive disease stage can be modeled in MS animal models. While acute and relapsing-remitting forms of experimental autoimmune encephalomyelitis (EAE), which are T cell dependent, are aptly suited to model relapsing-remitting phases of MS, other EAE models, especially the secondary progressive EAE stage in Biozzi ABH mice is better representing the secondary progressive phase of MS, which is refractory to many immune therapies. Besides EAE, the cuprizone model is rapidly gaining popularity to study the formation and progression of demyelinating CNS lesions without T cell involvement. Here, we discuss these two non-popular MS models. It is our aim to point out the pathological hallmarks of MS, and discuss which pathological aspects of the disease can be best studied in the various animal models available.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/bpa.12454

Multiple sclerosis animal models: a clinical and histopathological perspective

Microglia mediate chronic neuroinflammation following central nervous system (CNS) disease or injury, and in doing so, damage the local brain environment by impairing recovery and contributing to disease processes. Microglia are critically dependent on signaling through the colony-stimulating factor 1 receptor (CSF1R) and can be eliminated via administration of CSF1R inhibitors. Resolving chronic neuroinflammation represents a universal goal for CNS disorders, but long-term microglial elimination may not be amenable to clinical use. Notably, withdrawal of CSF1R inhibitors stimulates new microglia to fully repopulate the CNS, affording an opportunity to renew this cellular compartment. To that end, we have explored the effects of acute microglial elimination, followed by microglial repopulation, in a mouse model of extensive neuronal loss. Neuronal loss leads to a prolonged neuroinflammatory response, characterized by the presence of swollen microglia expressing CD68 and CD45, as well as elevated levels of cytokines, chemokines, complement, and other inflammatory signals. These collective responses are largely resolved by microglial repopulation. Furthermore, microglial repopulation promotes functional recovery in mice, with elevated plus maze performance matching that of uninjured mice, despite the loss of 80% of hippocampal neurons. Analyses of synaptic surrogates revealed increases in PSD95 and synaptophysin puncta with microglial repopulation, suggesting that these cells sculpt and regulate the synaptic landscape. Thus, our results show that short-term microglial elimination followed by repopulation may represent a clinically feasible and novel approach to resolve neuroinflammatory events and promote brain recovery.

/pdf/microglial-repopulation-resolves-inflammation-and-promotes-2926z8y8eo.pdf

Microglial repopulation resolves inflammation and promotes brain recovery after injury

The axon initial segment (AIS) is located at the proximal axon and is the site of action potential initiation. This reflects the high density of ion channels found at the AIS. Adaptive changes to the location and length of the AIS can fine-tune the excitability of neurons and modulate plasticity in response to activity. The AIS plays an important role in maintaining neuronal polarity by regulating the trafficking and distribution of proteins that function in somatodendritic or axonal compartments of the neuron. In this review, we provide an overview of the AIS cytoarchitecture, mechanism of assembly, and recent studies revealing mechanisms of differential transport at the AIS that maintain axon and dendrite identities. We further discuss how genetic mutations in AIS components (i.e., ankyrins, ion channels, and spectrins) and injuries may cause neurological disorders.

/pdf/axon-initial-segments-structure-function-and-disease-480xp9bg4z.pdf

Axon initial segments: structure, function, and disease

Axonal pathology is a key contributor to long-term disability in multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), but the mechanisms that underlie axonal pathology in MS remain elusive. Evidence suggests that axonal pathology is a direct consequence of demyelination, as we and others have shown that the node of Ranvier disassembles following loss of myelin. In contrast to the node of Ranvier, we now show that the axon initial segment (AIS), the axonal domain responsible for action potential initiation, remains intact following cuprizone-induced cortical demyelination. Instead, we find that the AIS is disrupted in the neocortex of mice that develop experimental autoimmune encephalomyelitis (EAE) independent of local demyelination. EAE-induced mice demonstrate profound compromise of AIS integrity with a progressive disruption that corresponds to EAE clinical disease severity and duration, in addition to cortical microglial reactivity. Furthermore, treatment with the drug didox results in attenuation of AIS pathology concomitantly with microglial reversion to a less reactive state. Together, our findings suggest that inflammation, but not demyelination, disrupts AIS integrity and that therapeutic intervention may protect and reverse this pathology. GLIA 2016;64:1190-1209.

Compromised axon initial segment integrity in EAE is preceded by microglial reactivity and contact

Inositol phospholipid metabolism during mito-gen-induced Schwann cell proliferation has been examined. Addition of axolemma- and myelin-enriched membrane fractions (AXL and MYE, respectively) to cultured Schwann cells stimulated 32P incorporation into phospha-tidylinositol 4-monophosphate [Ptdlns(4)P] and phospha-tidylinositol4,5-bisphosphate [Ptdlns(4,5)P2]. During the first 5 min of incubation with the mitogens, the amount of 32P incorporated into PtdIns(4)P and PtdIns(4,5)P2 was four- to fivefold above control values. The phosphorylation of the inositol phospholipids was dependent on the concentration of membrane mitogens and was maximal within 1 h. Schwann cells that were prelabeled with [3H]glycerol and then stimulated with AXL and MYE displayed a 30–70% increase in the amounts of [3H]PtdIns(4)P and [3H]PtdIns(4,5)P2 and a 60–80% increase in the amount of [3H]phosphatidic acid. A concomitant 20% decrease in the content of [3H]PtdIns was observed after stimulation. These results suggest that the increased metabolism of Ptdlns, Ptdlns(4)P, and Ptdlns(4,5)P2 may be one of the initial molecular events in the transduction of the mito-genic signal across the Schwann cell plasma membrane.

Schwann cell proliferation is accompanied by enhanced inositol phospholipid metabolism.

Quantitative determination of C6:0-C18:3 serum nonesterified fatty acids by gas-liquid chromatography.

We have postulated (APS-SPR, Apr. '72) that short and/or medium chain fatty acid accumulation is important in the pathogenesis of RS, causing mitochondrial swelling, cerebral edema, hypoglycemia and fatty viscera. This study reports gas chromatographic quantitation of serum free fatty acids (C8-C18) from 7 patients with RS, 8 controls (C) and 3 patients with acute and chronic liver failure (LF). Mean total free fatty acids (FAs) were much higher in all RS patients (9.5-185 mg%) vs C (0.35-2.75 mg%) and LF (0.69-3.0 mg%). Of greater significance was the 13-1500 fold increase in caprylic acid (C8) in 5 RS patients (vs C or LF). Because the sera were obtained at different stages of the disease the normal C8 levels in 2 patients may have been due to the very mobile nature of serum FAs. One 10 mo. old with coma had a C8 of 170 mg% (95.5% of total FA) on admission. Four hrs. after treatment with I.V. glucose and insulin the C8=0.15 mg% (normal range=0-0.12 mg%), but her status had not changed, necessitating 2 exchange transfusions 12 hrs. apart. C8 before the 2nd transfusion was 12 mg%. She recovered without sequelae and 12 days later C8= 0.08 mg%. All RS cases had appreciable elevations of other medium chain FAs (as high as 1.9 mg% C10). Long chain FAs were also elevated but only in proportion to the total FA. LF patients had no significant FA elevations. These findings implicate C8 (and possibly other medium chain FAs) as an important toxin in RS.

/pdf/fatty-acids-in-reye-s-syndrome-1a9vxqjmt1.pdf

Fatty acids in reye“s syndrome

Fatty acids in reyes syndrome

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