Elsevier

Neurobiology of Aging

Volume 27, Issue 9, September 2006, Pages 1298-1307
Neurobiology of Aging

Differences in the early inflammatory responses to toxin-induced demyelination are associated with the age-related decline in CNS remyelination

https://doi.org/10.1016/j.neurobiolaging.2005.06.008Get rights and content

Abstract

CNS remyelination occurs more rapidly in young adult rats than in old rats. Since the inflammatory response initiated by demyelination is an important trigger for remyelination, we address whether ageing changes in remyelination are associated with changes in the inflammatory response. Using a toxin model of demyelination, where the inflammatory response largely comprises macrophages, we show that there is a delay in both recruitment and activation of OX-42+ and macrophage scavenger receptor B+ macrophages following demyelination in older rats (10–13 months) compared to young rats (8–10 weeks). This difference is associated with a slower onset of increased expression of several chemokine mRNAs. However, many inflammatory cytokines have similar mRNA expression patterns, with the exception of IL-1β, IL-6 and TNF-α, which have prolonged expression in the older animals. Differences in IL-1β mRNA expression, a cytokine specifically implicated in CNS remyelination, are not reflected in differences in protein expression detected by immunocytochemistry. These data relate the age-associated delay in remyelination efficiency to changes in the macrophage and inflammatory mediator response to demyelination.

Introduction

Remyelination, the process in which new myelin sheaths are restored to demyelinated axons, is one of the few spontaneous regenerative processes that occur within the adult mammalian CNS [11]. However, although this helpful regenerative process can occur in demyelinating diseases such as multiple sclerosis [21], [30], it is not an invariable consequence of demyelination and there are many occasions where it fails to occur or is incomplete [6], [31]. Identifying factors that affect the efficiency of remyelination will help explain why remyelination fails and assist in identifying approaches by which it might be enhanced therapeutically. One of the major factors affecting remyelination is ageing; like many regenerative processes the efficiency of remyelination declines throughout adulthood [12], [13], [35], [36].

Several models of demyelination have been employed to study the complex signaling environment of remyelination. Those based on toxin-induced demyelination have proved especially useful since toxin exposure generally produces acute demyelination that is clearly separated from the ensuing regenerative phase. From studies using toxin models, it is clear that the inflammatory response to demyelination is important for successful remyelination, a view that can be obscured in the viral and immune models where inflammation clearly contributes to the demyelination. For example, a robust macrophage response and rapid clearance of the myelin debris generated by demyelination is associated with widespread remyelination [14], [23], while the absence of key inflammatory cells [5], [17], [18], [22] or inflammatory mediators [2], [3], [24] leads to remyelination impairment.

To identify what role the signaling environment and in particular inflammation might have in remyelination we have exploited the observation that the efficiency of this process declines with age [35]. By comparing rapid remyelination in young adult animals and slow remyelination in old adult animals it may be possible to identify important factors that either promote or inhibit remyelination efficiency. In an earlier study, we reported differences in the overall expression levels of macrophage scavenger receptor B mRNA following demyelination induced in young adult rats compared to that in older adult rats [16]. In young animals the onset of increased MSR-B mRNA expression occurred more quickly in young adult animals, although the levels of expression remained high for longer periods in old adult animals. In this study, we have addressed the following hypotheses: (1) the macrophage response to toxin-induced demyelination occurs more rapidly in young adult animals compared to older adults, and that (2) this difference reflects more rapid onset of increased expression of inflammatory mediators involved in macrophage recruitment and activation in young adults compared to old adults.

Section snippets

Animals

Female Sprague Dawley rats were obtained from Harlan (UK). Animal care procedures were in accordance with the guidelines set by the European Council directives (86/609/EEC) and the Home Office, Animals Scientific Procedures Act (1986, UK).

Spinal cord demyelination lesion

The animals were divided into two age groups: 8–10 week (young adult) and 10–13 month (old adult). Under halothane anaesthesia two foci spinal cord demyelination were created by direct injection of 1 μl 1% lysolecithin into both the dorsal and ventral

The rate of macrophage accumulation in acute areas of demyelination is reduced in older animals

Following induction of focal demyelination by injection of lysolecithin, cells of the microglia/macrophage lineage were identified by immunofluorescent staining with antibody against OX-42. The normal CNS white matter away from the site of lysolecithin injection contained scattered OX-42+ cells. These cells had the typical morphology of quiescent ramifying microglial cells with small cell bodies and numerous short processes (Fig. 1A). The lesioned area was readily recognizable because of the

Discussion

In common with all regenerative processes in mammals, the efficiency of remyelination decreases with ageing [12]. Determining the basis of this decline is likely to shed light on the mechanisms of remyelination, which in turn will inform future therapeutic developments for promoting remyelination in clinical demyelinating disease such as MS. In earlier studies, we have shown that the age-associated decrease in remyelination efficiency is associated with a decrease in recruitment of OPCs into

Acknowledgements

The work described in this paper has been supported by grants from The Wellcome Trust, Research into Ageing, The Barnwood House Trust and the European Union (Commission of the European Communities, specific RTD program “Quality of life and Management of Living Resources”, QLK6-CT-2000-00179, “The role of neurosteroids in healthy ageing: therapeutical perspectives”).

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