Axonal damage in acute multiple sclerosis lesions

Ferguson, Betsy; Matyszak, Malgosia K.; Esiri, Margaret M.; Perry, V. Hugh

doi:10.1093/brain/120.3.393

Cited by 1,408 publications

(932 citation statements)

References 4 publications

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“…9 Similarly, LPS systemic challenge leads to axon injury in EAE rats, as shown here following AdIL-1b challenge, and emphasizing the potential role of systemic inflammation in the deterioration of chronic MS lesions, which are responsible for the permanent disability in MS patients. 14,36 Similar effects of AdIL-1b have been shown in a model of Parkinson's disease where central and systemic IL-1b expression exacerbates neurodegeneration in 6-OHDA-injected rats. 15 The data presented here suggest a role specifically for systemic IL-1b in lesion reactivation.…”

Section: Discussionmentioning

confidence: 59%

Magnetic Resonance Imaging Reveals Therapeutic Effects of Interferon-Beta on Cytokine-Induced Reactivation of Rat Model of Multiple Sclerosis

Serres

Bristow

Pablos

et al. 2013

J Cereb Blood Flow Metab

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Interferon-b (IFN-b) drugs are considered to derive their beneficial effects on multiple sclerosis (MS) progression via their antiinflammatory properties, but the precise mechanism of action remains unclear. Here, we sought to discover how IFN-b impacts on inflammation-associated aggravation of MS-like lesions in rat. Animals with dormant focal experimental allergic encephalomyelitis (EAE) lesions were challenged intravenously with a replication-deficient adenovirus vector carrying interleukin (IL)-1b cDNA (AdIL-1b). Aggravation of inflammation and demyelination within the focal EAE lesion was observed after AdIL-1b injection with associated changes in tissue structure detected by diffusion and magnetization transfer imaging. Postgadolinium-DTPA T 1 -weighted images revealed contrast enhancement in the ipsilateral meninges, indicating breakdown of the blood-cerebrospinal fluid barrier, and increased left/right regional cerebral blood volume ratio was also observed after AdIL-1b injection. To determine the role of IFN-b on reactivation of the EAE lesion, rats were treated with therapeutic doses of IFN-b and focal EAE lesions showed significantly reduced reactivation in response to systemic AdIL-1b injection. In conclusion, these findings indicate a central role for peripheral IL-1b expression in the mechanism of MS lesion reactivation and that the therapeutic effects of IFN-b may, at least in part, reflect suppression of the effects of peripheral inflammation on MS lesion pathogenesis.

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Section: Discussionmentioning

confidence: 59%

Magnetic Resonance Imaging Reveals Therapeutic Effects of Interferon-Beta on Cytokine-Induced Reactivation of Rat Model of Multiple Sclerosis

Serres

Bristow

Pablos

et al. 2013

J Cereb Blood Flow Metab

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“…We next investigated whether the axons in the ventral funiculus of the spinal cord were immunoreactive for APP, which accumulates in degenerating axons (Ferguson et al, 1997; Sherriff et al, 1994). Two‐month‐old P301S‐htau mice displayed a limited number of APP positive axons that were mostly in the marginal areas, which are normally populated by larger‐calibre axons (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Injured axons in the MS lesion initially show a focal mitochondrial dysmorphism and axonal swelling (Nikic et al, 2011) which subsequently develops into axonal truncation with terminal ovoids (Trapp et al, 1998). Injured axons in MS lesions accumulate amyloid precursor protein (APP), which is detectable only in axons with impaired fast axonal transport (Ferguson et al, 1997; Sherriff et al, 1994). The impairment of axonal transport may result from the recently demonstrated presence in MS lesions of hyperphosphorylated tau (Anderson et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Ossola

Zhao

Compston

et al. 2015

Glia

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Oligodendrocyte progenitor cell (OPC) differentiation is an important therapeutic target to promote remyelination in multiple sclerosis (MS). We previously reported hyperphosphorylated and aggregated microtubule‐associated protein tau in MS lesions, suggesting its involvement in axonal degeneration. However, the influence of pathological tau‐induced axonal damage on the potential for remyelination is unknown. Therefore, we investigated OPC differentiation in human P301S tau (P301S‐htau) transgenic mice, both in vitro and in vivo following focal demyelination. In 2‐month‐old P301S‐htau mice, which show hyperphosphorylated tau in neurons, we found atrophic axons in the spinal cord in the absence of prominent axonal degeneration. These signs of early axonal damage were associated with microgliosis and an upregulation of IL‐1β and TNFα. Following in vivo focal white matter demyelination we found that OPCs differentiated more efficiently in P301S‐htau mice than wild type (Wt) mice. We also found an increased level of myelin basic protein within the lesions, which however did not translate into increased remyelination due to higher susceptibility of P301S‐htau axons to demyelination‐induced degeneration compared to Wt axons. In vitro experiments confirmed higher differentiation capacity of OPCs from P301S‐htau mice compared with Wt mice‐derived OPCs. Because the OPCs from P301S‐htau mice do not ectopically express the transgene, and when isolated from newborn mice behave like Wt mice‐derived OPCs, we infer that their enhanced differentiation capacity must have been acquired through microenvironmental priming. Our data suggest the intriguing concept that damaged axons may signal to OPCs and promote their differentiation in the attempt at rescue by remyelination. GLIA 2016;64:457–471

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“…Irreversible neuronal damage is a major pathological feature of multiple sclerosis (MS) and ranges from mild pathology to complete axonal transection [1,2]. The cause of neuronal damage is not yet elucidated, but autoreactive B and T cells directed against neuronal antigens could conceivably be instrumental [3].…”

Section: Introductionmentioning

confidence: 99%

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

et al. 2008

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Drainage of central nervous system (CNS) antigens to the brain-draining cervical lymph nodes (CLN) is likely crucial in the initiation and control of autoimmune responses during multiple sclerosis (MS). We demonstrate neuronal antigens within CLN of MS patients. In monkeys and mice with experimental autoimmune encephalomyelitis (EAE) and in mouse models with non-inflammatory CNS damage, the type and extent of CNS damage was associated with the frequencies of CNS antigens within the cervical lymph nodes. In addition, CNS antigens drained to the spinal-cord-draining lumbar lymph nodes. In human MS CLN, neuronal antigens were present in pro-inflammatory antigen-presenting cells (APC), whereas the majority of myelin-containing cells were anti-inflammatory. This may reflect a different origin of the cells or different drainage mechanisms. Indeed, neuronal antigen-containing cells in J Mol Med (2009) human CLN did not express the lymph node homing receptor CCR7, whereas myelin antigen-containing cells in situ and in vitro did. Nevertheless, CLN from EAE-affected CCR7-deficient mice contained equal amounts of myelin and neuronal antigens as wild-type mice. We conclude that the type and frequencies of CNS antigens within the CLN are determined by the type and extent of CNS damage. Furthermore, the presence of myelin and neuronal antigens in functionally distinct APC populations within MS CLN suggests that differential immune responses can be evoked.

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Axonal damage in acute multiple sclerosis lesions

Cited by 1,408 publications

References 4 publications

Magnetic Resonance Imaging Reveals Therapeutic Effects of Interferon-Beta on Cytokine-Induced Reactivation of Rat Model of Multiple Sclerosis

Magnetic Resonance Imaging Reveals Therapeutic Effects of Interferon-Beta on Cytokine-Induced Reactivation of Rat Model of Multiple Sclerosis

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

Brain antigens in functionally distinct antigen-presenting cell populations in cervical lymph nodes in MS and EAE

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