Our aim is to use modern in vivo microscopy techniques to reveal the cellular,
subcellular and molecular mechanisms that mediate neuroinflammatory tissue damage
in vivo. This approach can be illustrated using our recent insights into
the in vivo pathogenesis of immune-mediated axon damage as an example.
Immune-mediated axon damage plays a crucial role in inflammatory diseases of the
central nervous system (CNS) like multiple sclerosis (MS) [1], as we know by now that the number of axons damaged by immune cells
critically determines the clinical disability of MS patients. However we still
understand very little about the process that leads to axon damage. Recently, we
have used a spinal in vivo imaging approach [2], [3] to investigate the pathogenesis of
immune-mediated axon damage in an animal model of multiple sclerosis. By time-lapse
imaging of fluorescently labeled axons we could follow the slow and spatially
restricted degeneration of axons in inflammatory CNS lesions. This “focal axonal
degeneration” appears to be a novel type of axonal degeneration that is
characterized by intermediate stages that can persist for several days and progress
either to the degeneration or full recovery of the affected axons [4].
We are currently addressing the following key aspects of the axon degeneration
process using in vivo microscopy: First, to identify the molecular mechanisms
that drive axonal degeneration, we now reveal the actions of key damage mediators,
in particular the influx of calcium and the release of reactive species, in
vivo. This allows us to study which molecular effector pathways are
activated in neuroinflammatory lesions and determine how their activation is
regulated. Second, to better understand the relation between structural and
functional axon damage in neuroinflammatory lesions, we directly measure axonal
transport in neuroinflammatory lesions. Our results identify an early stage of
axonal dysfunction that precedes the structural manifestations of axon damage and
might help to explain the often short-lasting deficits observed during the
relapsing-remitting phase of multiple sclerosis.
Using these examples, I hope to illustrate how recent advances in light microscopy
can help us to reveal and mechanistically dissect nervous system damage as it
happens in the living CNS. We believe that these insights will help us to develop
targeted strategies to prevent nerve cell damage in neuroinflammatory conditions
like multiple sclerosis.
