Highlight Publication December 2008

Robert Adalbert1, Antal Nogradi2, Elisabetta Babetto1, Lucie Janeckova1, Simon A. Walker1, Martin Kerschensteiner3, Thomas Misgeld4 and Michael P. Coleman1 (In press)
Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies.
Brain  (Available online 5th December 2008)
http://dx.doi.org/10.1093/brain/awn312

1The Babraham Institute, Babraham Research Campus, Babraham, Cambridge, CB22 3AT UK
2 Laboratory of Neuromorphology, Department of Ophthalmology, University of Szeged, H-6720 Szeged, Hungary, 3 Institute of Clinical Neuroimmunology, Ludwig-Maximilians University
4 Institute of Neuroscience, Technical University Munich, Munich, Germany

Lay description

There are three pathological hallmarks of Alzheimer’s disease (AD): neurofibrillary tangles, amyloid plaques and dystrophic neurites.  Despite being described over a century ago (Fischer, O. 1907), and being well represented in mouse models of familial AD, dystrophic neurites have received by far the least attention of these hallmarks.  Only in the last few years has it become clear that they comprise both axons and dendrites that become grossly swollen or misshapen.  Their relationship to synapse loss, a very early event in AD accounting for cognitive decline, has been entirely unclear.  Specifically, it is important to determine whether axons and dendrites become interrupted at these swellings and whether this leads to Wallerian degeneration of distal axons and a cellular response to axon damage signals. 

We addressed these questions by crossing a transgenic mouse that develops amyloid plaques and dystrophic neurites, with another transgenic mouse where a small subset of neurons is fluorescently labelled.  This simplifies the images obtained from nervous system tissue by about tenfold. Consequently, thicker sections can be used in combination with confocal imaging methods to follow axons and dendrites over hundreds of microns to gain information about other parts of the same cell.  Such long-range imaging, while essential to see, quite literally, the ‘bigger picture’ has never been applied before to AD pathology, nor indeed to most other neurodegenerative disorders.

In contrast to earlier expectations, swollen axons and distorted dendrites are only very rarely interrupted even months after plaques and dystrophies first appear.  Distal axons and dendrites remain morphologically normal, which indicates that intracellular transport and neuronal metabolism must be continuing at levels compatible with the survival of each of these cellular compartments.  Moreover, cell bodies show no hint of the typical response to an axon damage signal.   By retaining the bulk of its normal axonal, dendritic and somatic components, these cells retain the first requirements for functional recovery, a result which had seemed unlikely when axons are swollen ten or twenty times their normal diameter. 

About the lead author

Robert Adalbert obtained his PhD degree from the University of Szeged, Hungary where he studied the role of intracellular calcium homeostasis in motor neurone degeneration. He joined Michael Coleman’s lab as a postdoc in Cologne, Germany and moved with the same lab to the Babraham Institute in 2003. He characterised the phenotype of WldS rats and worked on axon degeneration in motor neurone disease before beginning this study which investigated the role of axon pathology in Alzheimer’s disease.  

A press release relating to this publication is listed on the News 2008 webpage (opens in a new window).