A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis

Abstract

In multiple sclerosis, a common inflammatory disease of the central nervous system, immune-mediated axon damage is responsible for permanent neurological deficits. How axon damage is initiated is not known. Here we use in vivo imaging to identify a previously undescribed variant of axon damage in a mouse model of multiple sclerosis. This process, termed 'focal axonal degeneration' (FAD), is characterized by sequential stages, beginning with focal swellings and progressing to axon fragmentation. Notably, most swollen axons persist unchanged for several days, and some recover spontaneously. Early stages of FAD can be observed in axons with intact myelin sheaths. Thus, contrary to the classical view, demyelination-a hallmark of multiple sclerosis-is not a prerequisite for axon damage. Instead, focal intra-axonal mitochondrial pathology is the earliest ultrastructural sign of damage, and it precedes changes in axon morphology. Molecular imaging and pharmacological experiments show that macrophage-derived reactive oxygen and nitrogen species (ROS and RNS) can trigger mitochondrial pathology and initiate FAD. Indeed, neutralization of ROS and RNS rescues axons that have already entered the degenerative process. Finally, axonal changes consistent with FAD can be detected in acute human multiple sclerosis lesions. In summary, our data suggest that inflammatory axon damage might be spontaneously reversible and thus a potential target for therapy.

Neuronal expression of pathological tau accelerates oligodendrocyte progenitor cell differentiation

“…This may be due to lysolecithin‐induced depletion of myelin‐derived trophic support to axons, which in the case of already damaged P301S‐htau axons resulted in marked degeneration. Indeed Nikic et al(2011) have described that in an experimental model of MS axons showing signs of injury such as swelling and dystrophic mitochondria, can recover if they retain the myelin wrapping. To determine whether the axonal degeneration observed in P301S‐htau mice may have influenced the OPCs maturation in vivo , we investigated the functionality of OPCs isolated from 10‐ to 12‐day old mice.…”

“…Thus, enhancing remyelination, and particularly OPC differentiation, is an important therapeutic strategy to promote neuroprotection in the progressive stage of MS. 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).…”

“…Thus, the presence of hyperphosphorylated tau can be reversible and is not necessarily a precursor to insoluble aggregated forms. Reversible injury may also be a sign of early axonal degeneration in demyelinated lesions, as demonstrated in a mouse model of inflammation‐driven demyelination where some axons with focal swelling and dysmorphic mitochondrial recover spontaneously (Nikic et al, 2011). Thus, myelin can rescue damaged axons by stabilising the cytoskeleton, releasing trophic factors, and providing a source of energy such as lactate (Franklin et al, 2012; Lee et al, 2012).…”

In vivo imaging reveals rapid astrocyte depletion and axon damage in a model of neuromyelitis optica‐related pathology

“…Percentage of cell loss was defined as percentage of cells that lost >50% of their fluorescence, which was accompanied by clear changes in morphology (rounding, process blebbing). Axon morphology in a neuroinflammatory setting was staged as described previously 21, 22. Only axons that were observable across all time points during the experiment over at least 50 µm were analyzed.…”

“…Here, we use an in vivo two‐photon imaging approach to the mouse spinal cord that we previously established20, 21, 22 to gain insight into AQP4‐Ig‐mediated lesion formation. We found that AQP4‐Ig‐containing samples obtained from NMO patients (as well as a recombinant AQP4‐IgG from a clonotypic plasma blast present in the CSF of an NMO patient) caused acute, dose‐dependent and (human) complement‐mediated loss of astrocytes when applied at the pial surface of the spinal cord at IgG concentrations found intrathecally in NMO 23.…”