Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

Zhu, Bing; Luo, Laihui; Moore, George R.; Paty, Donald W.; Cynader, Max S.

doi:10.1016/s0002-9440(10)64298-8

Cited by 110 publications

(88 citation statements)

References 62 publications

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“…29 At the histological level, neuronal injury detected by dendritic beading was observed in Lewis rats immunized with MBP. 30 Finally, at the electrophysiological level, motor and sensory transmission defects in SJ/L mice corresponded with the appearance of neurological deficits and occurred in both the inflammatory period of the acute attack as well as in the chronic demyelinating stages. 31 This study indicated that defects in synaptic function, and not solely demyelination, resulted in clinical symptoms.…”

Section: Discussionmentioning

confidence: 94%

T-Cell-Mediated Disruption of the Neuronal Microtubule Network

Shriver

Dittel

2006

The American Journal of Pathology

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During the course of the central nervous system autoimmune disease multiple sclerosis (MS), damage to myelin leads to neurological deficits attributable to demyelination and conduction failure. However, accumulating evidence has indicated that axonal injury is also a predictor of MS clinical disease. Using the animal model of MS, experimental autoimmune encephalomyelitis (EAE), we examined whether axonal dysfunction occurred early in disease and correlated with disease symptoms. We tracked axons during EAE by using transgenic mice that express yellow fluorescent protein (YFP) in neurons. At the onset of disease, we observed a loss of YFP fluorescence in the spinal cord in areas that coincided with immune cell infiltration, before prominent demyelination. These inflammatory lesions also exhibited evidence of axonal injury but not axonal loss. During the recovery phase of EAE, the return of YFP fluorescence occurred in parallel with the resolution of inflammation. Using in vitro cultured neurons expressing YFP, we demonstrated that encephalitogenic T cells alone directed the destabilization of microtubules within neurites , resulting in a change in the pattern of YFP fluorescence. This study provides evidence that encephalitogenic T cells directly cause reversible axonal dysfunction at the onset of neurological deficits during an acute central nervous system inflammatory attack.

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Section: Discussionmentioning

confidence: 94%

T-Cell-Mediated Disruption of the Neuronal Microtubule Network

Shriver

Dittel

2006

The American Journal of Pathology

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“…Positive effects on remyelination and also neuroprotection are obtained by T4 administration in DA rats affected by EAE. This is a model of chronic relapsing-remitting EAE, which is characterized by extensive demyelination (35) and axonal, dendritic, and synaptic damage (36). When administered during the acute phase of the disease, T4 favors lineage toward oligodendrocytes, as indicated by increased expression of the OPC marker PDGF␣R, increases expression of MBP, and favors myelin sheath reorganization, which returns to a thickness comparable to that in control rats.…”

Section: Discussionmentioning

confidence: 99%

Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease

Fernández

Giuliani

Pirondi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

128

101

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Chronic disabilities in multiple sclerosis are believed to be due to neuron damage and degeneration, which follow remyelination failure. Due to the presence of numerous oligodendrocyte precursors inside demyelination plaques, one reason for demyelination failure could be the inability of oligodendrocyte precursor cells to turn into myelinating oligodendrocytes. In this study, we show that thyroid hormone enhances and accelerates remyelination in an experimental model of chronic demyelination, i.e., experimental allergic encephalomyelitis in congenic female Dark Agouti rats immunized with complete guinea pig spinal cord. Thyroid hormone, when administered during the acute phase of the disease, increases expression of platelet-derived growth factor ␣ receptor, restores normal levels of myelin basic protein mRNA and protein, and allows an early and morphologically competent reassembly of myelin sheaths. Moreover, thyroid hormone exerts a neuroprotective effect with respect to axonal pathology.neuroprotection ͉ multiple sclerosis ͉ oligodendrocyte precursor cells ͉ axonal pathology ͉ rat M ultiple sclerosis (MS) is a disorder of the central nervous system (CNS) that manifests as acute focal inflammatory demyelination with limited remyelination, usually culminating in chronic multifocal sclerotic plaques (1). Early axonal injury and loss followed by neuron distress (2) and death (3) occur in MS (4-6), accounting for brain and spinal cord atrophy. Irreversible axonal damage is an essential cause of nonremitting sensory, motor, and cognitive disabilities in MS (7). Although remyelination occurs in most experimental models of demyelination, this beneficial process is undoubtedly inadequate in MS. The reasons for this inadequacy are unknown, also because the oligodendrocyte precursor cells (OPCs), the cell population that is considered to be the most important source of remyelinating oligodendrocytes in the adult CNS (8-10), are present in early (fresh) demyelinating lesions in MS (11, 12).There are many possible speculative explanations for remyelination failure in MS (9, 10), including quantitatively inadequate recruitment and͞or differentiation of OPCs (13); axons not receptive to remyelination (14); and inappropriate support of growth factors by astrocytes and͞or other inflammatory cells (15), such as the extracellular microenvironment with regard to matrix proteins and adhesion molecules (16).Because the number of oligodendrocytes is greater than before demyelination in early MS, meaning that new oligodendrocytes are generated (17), another possibility is that OPCs are unable to turn into myelinating oligodendrocytes in chronic MS. Thus, extensive studies are under way to identify factors involved in OPC differentiation during remyelination. It is generally accepted that the process of remyelination represents a recapitulation of myelination during development, and so the key factors affecting the developmental maturation of OPCs into myelinating oligodendrocytes also should favor remyelination in the adult CNS. It ...

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“…Furthermore, PMCAs are localized to both synaptic terminals and dendrites (21). Thus, a reduction in PMCA activity may damage not only axons but also dendrites, which are affected during EAE (44). Indeed, it has been suggested that dendritic arborization of Purkinje cells in PMCA2 null mice is reduced as compared with their wild-type littermates (23).…”

Section: Discussionmentioning

confidence: 99%

Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury

et al. 2004

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Dysfunction and death of spinal cord neurons are critical determinants of neurological deficits in various pathological conditions, including multiple sclerosis (MS) and spinal cord injury. Yet, the molecular mechanisms underlying neuronal/axonal damage remain undefined. Our previous studies raised the possibility that a decrease in the levels of plasma membrane calcium ATPase isoform 2 (PMCA2), a major pump extruding calcium from neurons, promotes neuronal pathology in the spinal cord during experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and after spinal cord trauma. However, the causal relationship between alterations in PMCA2 levels and neuronal injury was not well established. We now report that inhibition of PMCA activity in purified spinal cord neuronal cultures delays calcium clearance, increases the number of nonphosphorylated neurofilament H (SMI-32) immunoreactive cells, and induces swelling and beading of SMI-32-positive neurites. These changes are followed by activation of caspase-3 and neuronal loss. Importantly, the number of spinal cord motor neurons is significantly decreased in PMCA2-deficient mice and the deafwaddler 2J , a mouse with a functionally null mutation in the PMCA2 gene. Our findings suggest that a reduction in PMCA2 level or activity leading to delays in calcium clearance may cause neuronal damage and loss in the spinal cord.Keywords autoimmune disease; ATP2B2; excitotoxicity; cytoskeleton Neuronal and axonal dysfunction and loss have increasingly received attention as important contributors to neural decline in various central nervous system (CNS) disorders, including MS and spinal cord trauma. MS is a CNS disease that may initially show a relapsing-remitting course but finally leads to permanent neurological impairment (1,2). Classically, demyelination of structurally intact axons was considered to be the main cause of clinical symptoms and neural deficits in MS. However, recent studies indicate that axonal dysfunction is already evident at the earliest clinical stages of MS, and axonal transection or loss may be the cause of persistent, irreversible disability at later phases of the disease when remissions no longer occur (3-5).

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Dendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis

Cited by 110 publications

References 62 publications

T-Cell-Mediated Disruption of the Neuronal Microtubule Network

T-Cell-Mediated Disruption of the Neuronal Microtubule Network

Thyroid hormone administration enhances remyelination in chronic demyelinating inflammatory disease

Plasma membrane calcium ATPase deficiency causes neuronal pathology in the spinal cord: a potential mechanism for neurodegeneration in multiple sclerosis and spinal cord injury

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