Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system. Due to its high prevalence, MS is the leading cause of non-traumatic neurological disability in young adults in the United States and Europe. The clinical disease course is variable and starts with reversible episodes of neurological disability in the third or fourth decade of life. This transforms into a disease of continuous and irreversible neurological decline by the sixth or seventh decade. Available therapies for MS patients have little benefit for patients who enter this irreversible phase of the disease. It is well established that irreversible loss of axons and neurons are the major cause of the irreversible and progressive neurological decline that most MS patients endure. This review discusses the etiology, mechanisms and progress made in determining the cause of axonal and neuronal loss in MS.

Figure 1. Immune-mediated demyelination and axonal transection

Axonal ovoids are hallmark of transected axons. Abundant axonal ovoids were detected in MS tissue (a) when stained for myelin protein (red) and axons (green). There are areas of demyelination (arrowheads), mediated by microglia and hematogenous monocytes. One of the axons ends in a large swelling (arrow) or axonal retraction bulb (arrow). (b-c) Schematic of axonal response during and following transection. Demyelination is an immune-mediated or immune cell assisted process leading to axonal transaction. When transected, the distal end of the axon rapidly degenerates while the proximal end connected to the neuronal cell body survives and transported organelles accumulate at the transection site and form an ovoid (arrows). (Reproduced from(Trapp and Nave, 2008)

Figure 2. Ultrastructural changes in MS axons

The electron micrograph in (a) contains four axons (Ax1-Ax4) at the edge of a demyelinated lesion. The myelinated axon (Ax1) has normal-appearing axoplasm (b), with intact and appropriately oriented neurofilaments. Axoplasm of demyelinated Ax2 (c) is also intact, but neurofilament spacing is significantly reduced. Neurofilaments in demyelinated Ax3 (d) are fragmented and they are barely detectable in demyelinated Ax4. Scale Bar b-d = 200 nm. (Reproduced from (Dutta et al., 2006)

Figure 3. Magnetization transfer ratios (MTR) and T1 contrast ratios linearly correlate with the percentage of Na⁺/K⁺ ATPase-positive axons in chronic MS lesions

Chronically demyelinated lesions stained for Na⁺/K⁺ ATPase (green) varied from nearly 100% (a) to zero (b), in neurofilament (red). Many axons without Na⁺/K⁺ ATPase had increased diameters (b). A comparison of the percentage of Na⁺/K⁺ ATPase-positive axons in chronically demyelinated MS lesions correlated with quantitative postmortem magnetization transfer ratio (MTR, p<0.0001, c) and T1 contrast ratios, (p<0.0006, d). Each data point is from a single lesion and each unique color-symbol combination denotes one of the brains studied. Scales bars = 5μm. (Reproduced from (Young et al., 2008)

Figure 4. Upregulation of a CNTF-mediated Neuroprotection in MS Motor Cortex

mRNA encoding CNTF and multiple members of the CNTF signaling pathway are increased in MS cortex (a). (b) Schematic representation of the CNTF signaling pathway members which were increased in MS cortex. Red denotes increased in MS cortex. (Reproduced from (Dutta et al., 2007)

Figure 5. Cortical Demyelination and neuronal pathology

Three patterns of cortical demyelination (orange) occur in MS brains. Type I lesions occur at the leukocortical junction and demyelinate both white and gray matter (a). Type II lesions are small perivascular lesions (b). Type III lesions extended into the cortex from the pial surface and often involve multiple gyri (c). (d) Cortical demyelination occurs without significant infiltration of hematogenous leukocytes, which is schematically depicted in a Type I lesion (ctx, cortex; wm, white matter). (e) Axons and dendrites are transected (arrowheads) during cortical demyelination. (f) Apoptotic neurons (arrows), identified by tunnel staining, are increased in demyelinated cortex. (Reproduced from (Peterson et al., 2001; Peterson et al., 2005; Trapp and Nave, 2008)