ReviewAxonal and neuronal pathology in multiple sclerosis: What have we learnt from animal models
Introduction
Although multiple sclerosis (MS) has originally been defined as an inflammatory demyelinating disease, it was already noted in its earliest pathological descriptions that axons and neurons are also affected and that axonal injury and loss is a major substrate for permanent neurological deficit of the patients (for review see Kornek and Lassmann, 1999). The situation is best exemplified by a statement of Marburg (1906) in his study on the lesions of acute multiple sclerosis. He claimed that multiple sclerosis is a demyelinating disease with relative preservation of axons. However, he then added that emphasis has to laid upon the term “relative” and that a variable degree of axonal loss is present in every multiple sclerosis lesion. Thus, in the literature published between 1880 and 1930 much attention was paid to axonal pathology in MS and it became clear that axonal loss within the lesions is variable, but very severe in selected cases, that acute axonal injury is associated with inflammatory macrophage infiltration and that there are some, but rather inefficient attempts of axonal regeneration. Furthermore, by analysing clinico-pathological correlation in patients with spinal cord lesions, it became clear that permanent neurological deficit is more related to axonal loss than to demyelination (Kornek and Lassmann, 1999). However, when it was found that a disease, with similarities to MS, can be induced by active sensitisation of experimental animals with nervous system tissue, isolated myelin or purified myelin proteins, interest focused on demyelination and the importance of axonal pathology was ignored for many decades. Emphasis on axonal injury and loss in MS brains was reintroduced, when new technologies in magnetic resonance imaging (MRI) revealed changes, most likely consistent with profound axonal injury and loss, leading to a boom of neuropathological studies during the last two decades, which focused on this issue (Kornek and Lassmann, 1999).
Section snippets
Key features of axonal and neuronal pathology in multiple sclerosis
As mentioned above, axonal injury and loss is present in all demyelinated lesions in MS, but their extent is variable. In chronic established lesions axonal density is reduced in average by 60–70% (Mews et al., 1998, Bjartmar et al., 2000). Acute axonal injury, as seen by the presence of axonal spheroids and end bulbs or detected by the focal accumulation of proteins, which are moved along the axon by fast axonal transport, is mainly seen in actively demyelinating lesions. However, even in
Axonal loss in lesions of autoimmune encephalomyelitis is similar to that seen in MS lesions
Like in MS, axonal injury and loss is also pronounced in the lesions in experimental autoimmune encephalomyelitis. The extent of axonal loss, however, depends upon the species and strain of animals and the procedure of the induction of experimental autoimmune encephalomyelitis (EAE). Widespread axonal damage is seen in most EAE models, induced in mice by active sensitisation. In such lesions primary demyelination, although present, is sparse and axonal destruction with secondary demyelination
Experimental models reveal different mechanisms of axonal injury in inflammatory lesions of the central nervous system
Depending upon the experimental model different mechanisms of axonal injury in inflammatory lesions of the brain and spinal cord have been described. They involve mechanisms of adaptive immunity, mediated through T-lymphocytes and antibodies, as well as of innate immunity, mainly driven by activated macrophages and microglia.
Antibody mediated axonal or neuronal destruction
It is now well established that auto-antibodies, when they reach their target in the central nervous system under inflammatory conditions, lead to selective damage of their target cells (Linington et al., 1988). Auto-antibodies against molecules, expressed on the surface of neurons and axons, are thus potential candidates for mediating axonal or neuronal injury. Recently it was found that a subset of patients with multiple sclerosis mount an antibody response, which is directed against
Axonal and neuronal injury induced by toxic products produced by activated macrophages or microglia
In MS lesions axonal injury is closely associated with macrophages and microglia, which are seen in close contact with axons, that reveal acute axonal injury, such as the formation of axonal spheroids or a disturbance of fast axonal transport (Trapp et al., 1998, Ferguson et al., 1997). Activated macrophages and microglia produce a large array of toxic molecules, which may potentially induce axonal injury. They include proteo- and lipolytic enzymes, cytotoxic cytokines, excitotoxins and
Consequences of mitochondrial dysfunction and energy failure for axons and neurons
Energy deficiency has fatal consequences for axons (Trapp and Stys, 2009, Mahad et al., 2008b). The axonal Na+ pump is dependent upon the availability of ATP. Thus, in electrically active nerve fibers Na+ accumulates in the axonal cytoplasm in conditions of energy deficiency. Axonal Na+ is then replaced by calcium due to a reverse operation of the Na+/Ca++ exchanger, resulting in increasing Ca++ concentrations. Ca++ dependent proteases, such as calpains, are activated in such a condition and
Mechanisms of axonal and neuronal injury in inflammatory lesions of the central nervous system are in part different
Most studies on neurodegeneration in EAE and MS have so far focused on axons. During the last years, however, a model has been developed, which allows simultaneous and accurate evaluation of both axonal and neuronal injury. This model is based on the analysis of the optic nerve and the retina in EAE animals, specifically selected for their preferential affection of the optic system (Sättler et al., 2008). The advantages of this system for such studies are the rather simple anatomical
Conclusions
Degeneration of axons and neurons is an important feature of MS pathology and appears to be the major correlate for permanent clinical deficit in the patients. Experimental models show that in the context of inflammation axons and neurons can be destroyed by a variety of different mechanisms and that these mechanisms are in part different for axons and their respective cell bodies. In a complex disease such as MS it is likely that most of these different mechanisms play some pathogenetic role
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