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Multiple sclerosis (MS) is a chronic demyelinating and neuroinflammatory disease of the human central nervous system with complex pathoetiology, heterogeneous presentations and an unpredictable course of disease progression. There remains an urgent need to identify and validate a biomarker that can reliably predict the initiation and progression of MS as well as identify patient responses to disease-modifying treatments/therapies (DMTs). Studies exploring biomarkers in MS and other neurodegenerative diseases currently focus mainly on cerebrospinal fluid (CSF) analyses, which are invasive and impractical to perform on a repeated basis. Recent studies, replacing CSF with peripheral blood samples, have revealed that the elevation of serum neurofilament light chain (sNfL) in the clinical stages of MS is, potentially, an ideal prognostic biomarker for predicting disease progression and for possibly guiding treatment decisions. However, there are unresolved factors (the definition of abnormal values of sNfL concentration, the standardisation of measurement and the amount of change in sNfL concentration that is significant) that are preventing its use as a biomarker in routine clinical practice for MS. This updated review critiques these recent findings and highlights areas for focussed work to facilitate the use of sNfL as a prognostic biomarker in MS management. [ABSTRACT FROM AUTHOR]

They also ruled out the possibility of myelin thinning resulting neither from remyelination, (no myelin loss or oligodendrocyte death), nor from regeneration, (no increase in oligodendrocyte precursor cells or oligodendrocyte proliferation). Keywords: multiple sclerosis; neurodegeneration; unfolded protein response; demyelination; protein aggregation EN multiple sclerosis neurodegeneration unfolded protein response demyelination protein aggregation N.PAG N.PAG 5 03/26/21 20210324 NES 210324 Introduction Myelination is a fundamental molecular event within the vertebrate central nervous system (CNS) where oligodendrocytes wrap around axons to form a myelin sheath which allows rapid "saltatory" conduction of action potentials along the axons (Bercury and Macklin, [3]). These observations (Silva et al., [24]; Wu et al., [30]) suggest that myelin thinning is not exclusive to the loss of a single class of myelin proteins (e.g., PLP), but rather the reduction of multiple myelin proteins (e.g., PLP, MBP) contribute to myelin thinning. While demyelination and neurodegeneration are hallmark pathologies of many CNS diseases, including Multiple Sclerosis (MS), myelin thinning was not considered detrimental until recent years. [Extracted from the article]

Multiple Sclerosis (MS) is traditionally considered an autoimmune-mediated demyelinating disease, the pathoetiology of which is unknown. However, the key question remains whether autoimmunity is the initiator of the disease (outside-in) or the consequence of a slow and as yet uncharacterized cytodegeneration (oligodendrocytosis), which leads to a subsequent immune response (inside-out). Experimental autoimmune encephalomyelitis has been used to model the later stages of MS during which the autoimmune involvement predominates. In contrast, the cuprizone (CPZ) model is used to model early stages of the disease during which oligodendrocytosis and demyelination predominate and are hypothesized to precede subsequent immune involvement in MS. Recent studies combining a boost, or protection, to the immune system with disruption of the blood brain barrier have shown CPZ-induced oligodendrocytosis with a subsequent immune response. In this Perspective, we review these recent advances and discuss the likelihood of an inside-out vs. an outside-in pathoetiology of MS. [ABSTRACT FROM AUTHOR]

• CPZ-feeding caused differential oligodendrocytosis, demyelination and gliosis in the CNS. • More complex behavioural tasks detected subtle motor deficits. • Vestibular and cerebellar systems were associated with motor dysfunction. • CPZ-feeding did not alter nociceptive thresholds. Feeding cuprizone (CPZ) to mice causes demyelination and reactive gliosis in the central nervous system (CNS), hallmarks of some neurodegenerative diseases like multiple sclerosis. However, relatively little is known regarding the behavioural deficits associated with CPZ-feeding and much of what is known is contradictory. This study investigated whether 37 days oral feeding of 0.2% CPZ to young adult mice evoked sensorimotor behavioural changes. Behavioural tests included measurements of nociceptive withdrawal reflex responses and locomotor tests. Additionally, these were compared to histological analysis of the relevant CNS regions by analysis of neuronal and glial cell components. CPZ-fed mice exhibited more foot slips in walking ladder and beam tests compared to controls. In contrast, no changes in nociceptive thresholds to thermal or mechanical stimuli occurred between groups. Histological analysis showed demyelination throughout the CNS, which was most prominent in white matter tracts in the cerebrum but was also elevated in areas such as the hippocampus, basal ganglia and diencephalon. Profound demyelination and gliosis was seen in the deep cerebellar nuclei and brain stem regions associated with the vestibular system. However, in the spinal cord changes were minimal. No loss of oligodendrocytes, neurons or motoneurons occurred but a significant increase in astrocyte staining ensued throughout the white matter of the spinal cord. The results suggest that CPZ differentially affects oligodendrocytes throughout the CNS and induces subtle motor changes such as ataxia. This is associated with deficits in CNS regions associated with motor and balance functions such as the cerebellum and brain stem. [ABSTRACT FROM AUTHOR]

Cuprizone (CPZ)-feeding in mice induces atrophy of peripheral immune organs (thymus and spleen) and suppresses T-cell levels, thereby limiting its use as a model for studying the effects of the immune system in demyelinating diseases such as Multiple Sclerosis (MS). To investigate whether castration (Cx) can protect the peripheral immune organs from CPZ-induced atrophy and enable T-cell recruitment into the central nervous system (CNS) following a breach of the blood-brain barrier (BBB), three related studies were carried out. In Study 1, Cx prevented the dose-dependent reductions (0.1% < 0.2% CPZ) in thymic and splenic weight, size of the thymic medulla and splenic white pulp, and CD4 and CD8 (CD4/8) levels remained comparable to gonadally intact (Gi) control males. Importantly, 0.1% and 0.2% CPZ were equipotent at inducing central demyelination and glial activation. In Study 2, combining Cx with 0.1% CPZ-feeding and BBB disruption with pertussis toxin (PT) enhanced CD8+ T-cell recruitment into the CNS. The increased CD8+ T-cell level observed in the parenchyma of the cerebrum, cerebellum, brainstem and spinal cord were confirmed by flow cytometry and western blot analyses of CNS tissue. In Study 3, PT+0.1% CPZ-feeding to Gi female mice resulted in similar effects on the peripheral immune organs, CNS demyelination, and gliosis comparable to Gi males, indicating that testosterone levels alone were not responsible for the immune response seen in Study 2. The combination of Cx +0.1% CPZ-feeding+PT indicates that CPZ-induced demyelination can trigger an "inside-out" immune response when the peripheral immune system is spared and may provide a better model to study the initiating events in demyelinating conditions such as MS. [ABSTRACT FROM AUTHOR]

• Behavioural tests using the CPZ model focus mainly on motor, anxiety and cognition but not other common clinical symptoms in MS like pain or fatigue. • Most histological correlations associated with behavioural deficits were found to be inappropriate. • CPZ-feeding alone may be a useful tool to model some behavioural aspects of demyelinating diseases but it should not be regarded as a model of MS per se. The feeding of cuprizone (CPZ) to animals has been extensively used to model the processes of demyelination and remyelination, with many papers adopting a narrative linked to demyelinating conditions like multiple sclerosis (MS), the aetiology of which is unknown. However, no current animal model faithfully replicates the myriad of symptoms seen in the clinical condition of MS. CPZ ingestion causes mitochondrial and endoplasmic reticulum stress and subsequent apoptosis of oligodendrocytes leads to central nervous system demyelination and glial cell activation. Although there are a wide variety of behavioural tests available for characterizing the functional deficits in animal models of disease, including that of CPZ-induced deficits, they have focused on a narrow subset of outcomes such as motor performance, cognition, and anxiety. The literature has not been systematically reviewed in relation to these or other symptoms associated with clinical MS. This paper reviews these tests and makes recommendations as to which are the most important in order to better understand the role of this model in examining aspects of demyelinating diseases like MS. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is a demyelinating disease of the human central nervous system having an unconfirmed pathoetiology. Although animal models are used to mimic the pathology and clinical symptoms, no single model successfully replicates the full complexity of MS from its initial clinical identification through disease progression. Most importantly, a lack of preclinical biomarkers is hampering the earliest possible diagnosis and treatment. Notably, the development of rationally targeted therapeutics enabling pre-emptive treatment to halt the disease is also delayed without such biomarkers. Using literature mining and bioinformatic analyses, this review assessed the available proteomic studies of MS patients and animal models to discern (1) whether the models effectively mimic MS; and (2) whether reasonable biomarker candidates have been identified. The implication and necessity of assessing proteoforms and the critical importance of this to identifying rational biomarkers are discussed. Moreover, the challenges of using different proteomic analytical approaches and biological samples are also addressed. [ABSTRACT FROM AUTHOR]

Cuprizone (CPZ) preferentially affects oligodendrocytes (OLG), resulting in demyelination. To investigate whether central oligodendrocytosis and gliosis triggered an adaptive immune response, the impact of combining a standard (0.2%) or low (0.1%) dose of ingested CPZ with disruption of the blood brain barrier (BBB), using pertussis toxin (PT), was assessed in mice. 0.2% CPZ(±PT) for 5 weeks produced oligodendrocytosis, demyelination and gliosis plus marked splenic atrophy (37%) and reduced levels of CD4 (44%) and CD8 (61%). Conversely, 0.1% CPZ(±PT) produced a similar oligodendrocytosis, demyelination and gliosis but a smaller reduction in splenic CD4 (11%) and CD8 (14%) levels and no splenic atrophy. Long-term feeding of 0.1% CPZ(±PT) for 12 weeks produced similar reductions in CD4 (27%) and CD8 (43%), as well as splenic atrophy (33%), as seen with 0.2% CPZ(±PT) for 5 weeks. Collectively, these results suggest that 0.1% CPZ for 5 weeks may be a more promising model to study the 'inside-out' theory of Multiple Sclerosis (MS). However, neither CD4 nor CD8 were detected in the brain in CPZ±PT groups, indicating that CPZ-mediated suppression of peripheral immune organs is a major impediment to studying the 'inside-out' role of the adaptive immune system in this model over long time periods. Notably, CPZ(±PT)-feeding induced changes in the brain proteome related to the suppression of immune function, cellular metabolism, synaptic function and cellular structure/organization, indicating that demyelinating conditions, such as MS, can be initiated in the absence of adaptive immune system involvement. [ABSTRACT FROM AUTHOR]