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Monday

 

Widespread Synaptic Loss in MS




































Figure 1.
Schematic of the experimental design and results. Analysis of multiple sclerosis and control brain autopsies from three different brain regions for demyelination, spine and axon density. Table summarizes the results for normal-appearing grey matter and demyelinated lesions. Demyelinated lesions show both reduced spine and axon densities, while in normal-appearing grey matter spine densities are reduced but axon densities are not altered in comparison to controls. These results indicate that spine loss in multiple sclerosis is independent of axonal input and demyelination.

It has been estimated that the human brain comprises 8.6 × 1011 neurons that are connected by ×1014 synapses (Pakkenberg et al., 2003). These synapses decline in number during ageing and show accelerated loss in neurodegenerative diseases such as Alzheimer's disease (Selkoe, 2002).
However, whether synaptic loss also occurs in multiple sclerosis and, if so, how it relates to demyelination and axonal input, is unclear. In this issue of Brain, Jürgens et al. use elegant staining and imaging techniques to shed light on synaptic pathology in multiple sclerosis, and conclude that such pathology is widespread and occurs without coincident demyelination or axonal degeneration (Jürgens et al., 2016).

While multiple sclerosis was initially considered to be a chronic inflammatory disease that mainly affects white matter, it is now clear that grey matter pathology such as neuronal and axonal loss is equally widespread (Friese et al., 2014). Demyelinated areas in the hippocampi of multiple sclerosis brains show a consistent reduction in synaptic density (Dutta et al., 2011). Grey matter demyelination and accompanying neuronal demise contribute to permanent neurological disability in multiple sclerosis as revealed by their correlation with disease progression (Calabrese et al., 2013). Similarly, cognitive dysfunction is found in over 50% of patients with multiple sclerosis and can be attributed to grey matter pathology (Chiaravalloti and DeLuca, 2008). While all neuronal subcellular structures are affected in the disorder, it remains unclear which part of the neuron fails first and spurs degeneration of dependent structures, i.e. does inflammatory axonal transection result in neuronal cell body death, or do remote neurons degenerate as a result of diminished excitatory input from damaged presynaptic cells (Friese et al., 2014)? Notably, in Alzheimer's disease neuronal death is preceded by synaptic dysfunction and consequent synaptic loss (Selkoe, 2002). Therefore it is possible that early synaptic loss initiates neuronal death and disease progression also in multiple sclerosis. Determining the order of degeneration of subcellular structures (synapse, neuronal cell body, axon) has clinical implications, as treatments must not only keep neurons alive, but also maintain their synapses and axons in a functional state. First, we need to understand whether synaptic loss in multiple sclerosis is secondary to demyelination and axonal degeneration or whether it instead is an independent process.

To investigate the sequence of events in synaptic loss in multiple sclerosis grey matter, the research groups of Doron Merkler and Martin Kerschensteiner jointly applied a modified Golgi-Cox impregnation technique with high resolution confocal microscopy to brain autopsies. They analysed control cortex and normal-appearing as well as demyelinated multiple sclerosis cortex and quantified the density of dendritic spines, the morphological sites at which synapses are formed (Jürgens et al., 2016) (Fig. 1).

Schematic of the experimental design and results. Analysis of multiple sclerosis and control brain autopsies from three different brain regions for demyelination, spine and axon density. Table summarizes the results for normal-appearing grey matter and demyelinated lesions. Demyelinated lesions show both reduced spine and axon densities, while in normal-appearing grey matter spine densities are reduced but axon densities are not altered in comparison to controls. These results indicate that spine loss in multiple sclerosis is independent of axonal input and demyelination.

First, they investigated whether synaptic loss is associated with demyelination. By reconstructing single pyramidal neurons located in layers IV–VI of cortical brain tissue sampled from insular, frontotemporal and occipital lobes of up to eight control and eight multiple sclerosis brains, they revealed a reduction in spine density of more than 50% in both demyelinated and non-demyelinated normal-appearing grey matter of multiple sclerosis brains versus controls. This result illustrates that massive synaptic loss occurs independently of demyelination.

Second, to address the possibility that synapses are lost in multiple sclerosis brains owing to reduced synaptic input as a result of coincident axonal degeneration, Jürgens et al. analysed cortical axons that were tangentially orientated, indicating that they were afferent axons. As anticipated, demyelinated grey matter showed a reduction in cortical axon density, while surprisingly, normal-appearing grey matter in multiple sclerosis brains showed no alteration in axon density in comparison to control brains. This finding convincingly shows that there is no correlation between axon loss and reduced synaptic density. Therefore, the latter also occurs independently of synaptic input in multiple sclerosis. While this important neuropathological study is descriptive, it raises questions about the underlying pathophysiological mechanisms driving synapse loss that warrant further in-depth research. Indeed, a number of possible explanations for synapse loss in multiple sclerosis have recently been reported.

The mechanisms that determine the elimination of synapses, both in neurodegenerative diseases and also in the development of the nervous system, have been a longstanding research question. In development, synapse elimination is thought to result from divergent neuronal activity of axons competing for the same postsynaptic territory (Huberman et al., 2008). Strongly active synapses that result in postsynaptic activity will trigger the elimination of neighbouring less effective synapses. Signals that tag synapses for elimination have recently been identified within the classical complement cascade that has a fundamental role in the immune system (Stevens et al., 2007). Complement proteins localize to excess synapses and tag them for elimination, thereby ensuring precise synaptic circuits. Therefore, the function of complement proteins appears to be similar in the CNS and the immune system, as in both they opsonize cellular components for clearance by phagocytic cells, such as activated microglia in the CNS. Of note, neuroinflammation—which is abundant in multiple sclerosis brains (Dendrou et al., 2015) but also present to a lesser extent in most neurodegenerative diseases, including Alzheimer's disease—activates the classical complement cascade. Moreover, as CNS neurons lack or show very low expression of complement inhibitors, they might be particularly vulnerable to complement-tagged synaptic elimination during states of chronic inflammation. This raises the question of whether, similar to the scenario in the developing nervous system (Stevens et al., 2007), the classical complement cascade and activated microglia are responsible for pathological elimination of synapses in multiple sclerosis. If so, this loss of synapses could initiate neuronal loss that then drives disease progression. Of note, a recent study that compared complement component expression and activation in the hippocampi of patients with multiple sclerosis corroborated this notion (Michailidou et al., 2015). In accordance with the findings of Jürgens and co-workers, synaptic density was decreased in demyelinated but also in myelinated hippocampi compared to control brains. Additionally, the complement components C1q and the C3 activation products localized to synapses that were within reach of microglial cellular processes, implicating active synaptic elimination of complement-tagged synapses in multiple sclerosis.

Taken together, these results indicate that synaptic loss occurs widely and independently of demyelination and axonal degeneration in the grey matter of multiple sclerosis brains. While the pathophysiology remains enigmatic, there is circumstantial evidence that continuous and diffuse activation of the classical complement cascade might be involved in this process, which could drive neuronal loss and disability progression. This exciting finding warrants additional mechanistic investigations.

Story Source: The above story is based on materials provided by MEDSCAPE
Note: Materials may be edited for content and length


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