Brain Advance Access published online on December 5, 2008
Brain, doi:10.1093/brain/awn312
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Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies
1The Babraham Institute, Babraham Research Campus, Babraham, Cambridge, CB22 3AT UK, 2Laboratory of Neuromorphology, Department of Ophthalmology, University of Szeged, H-6720 Szeged, Hungary, 3Institute of Clinical Neuroimmunology, Ludwig-Maximilians University and 4Institute of Neuroscience, Technical University Munich, Munich, Germany
Correspondence to:
Correspondence to: Dr Michael Coleman, B540, The Babraham Institute, Babraham Research Campus, Babraham, Cambridge, CB22 3AT, UK E-mail: michael.coleman{at}bbsrc.ac.uk
Synapse loss precedes cell death in Alzheimer's disease, but the timing of axon degeneration relative to these events, and the causal relationships remain unclear. Axons become so severely dystrophic near amyloid plaques that their interruption, causing permanent loss of function, extensive synapse loss, and potentially cell death appears imminent. However, it remains unclear whether axons are truly interrupted at plaques and whether cell bodies fail to support their axons and dendrites. We traced TgCRND8 mouse axons longitudinally through, distal to, and proximal from dystrophic regions. The corresponding neurons not only survived but remained morphologically unaltered, indicating absence of axonal damage signalling or a failure to respond to it. Axons, no matter how dystrophic, remained continuous and initially morphologically normal outside the plaque region, reflecting support by metabolically active cell bodies and continued axonal transport. Immunochemical and ultrastructural studies showed dystrophic axons were tightly associated with disruption of presynaptic transmission machinery, suggesting local functional impairment. Thus, we rule out long-range degeneration axons or dendrites as major contributors to early synapse loss in this model, raising the prospect of a therapeutic window for functional rescue of individual neurons lasting months or even years after their axons become highly dystrophic. We propose that multi-focal pathology has an important role in the human disease in bringing about the switch from local, and potentially recoverable, synapse loss into permanent loss of neuronal processes and eventually their cell bodies.
Key Words: Alzheimer's disease; axonal dystrophy; axonal damage signalling; TgCRND8; synapse dysfunction
Abbreviations: Aβ, amyloid (βeta peptide; APP, amyloid precursor protein; CFP, cyan fluorescent protein; ex., excitation; em., Emission; YFP, yellow fluorescent protein
Received March 20, 2008. Revised October 30, 2008. Accepted October 30, 2008.
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