Preactive multiple sclerosis lesions offer novel clues for neuroprotective therapeutic strategies

For the development of novel central nervous system (CNS) drugs to promote neuroprotection, it is helpful to gain a betterunderstanding of natural neuroprotective phenomena. Microglia play key roles in endogenous neuroprotective pathways and their activation is a common theme in several neurodegenerative disorders. Yet, while it is widely appreciated that activated microglia can have neuroprotective qualities, their contribution to tissue destruction and neurodegeneration within the CNS is equally obvious. This apparent duality in microglial functions renders it difficult to determine whether microglial activation under certain conditions is something to counteract, or to support. Also, it is far from clear which microglial functions support neuroprotection, and which support destruction. Here, we review evidence that a special phenomenon in multiple sclerosis (MS) patients offers a unique possibility to study polarized protective functions of microglia. During MS, small clusters of activated microglia frequently emerge throughout normalappearing white matter. Several lines of evidence suggest that these clusters, which are referred to as preactive MS lesions, represent a reversible first stage in the development of inflammatory, demyelinating MS lesions. Progression onto this final destructive stage may occur but, importantly, does not seem to be inevitable. Instead, resolution of preactive lesions is probably the rule rather than the exception. For as long as preactive lesions remain non-infiltrated by peripheral lymphocytes, they reflect a local neuroprotective and reparative response. A critical factor in the emergence of preactive lesions is oligodendrocyte stress, which leads to accumulation of factors such as small heat shock proteins. At least some of these can induce an immune-regulatory response in neighboring microglia. A closer understanding of the molecular make-up of preactive MS lesions, of the signals which cause microglial activation, and of the protective mediators produced by microglia in this context, will help uncover novel clues for neuroprotective therapeutic strategies with relevance for clinical applications well beyond the field of MS alone.