Severely dystrophic axons at amyloid plaques remain continuous and connected to viable cell bodies

Robert Adalbert, Antal Nogradi, Elisabetta Babetto, Lucie Janeckova, Simon A. Walker, Martin Kerschensteiner, Thomas Misgeld, Michael P. Coleman

Research output: Contribution to journalArticlepeer-review

132 Scopus citations


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.

Original languageEnglish
Pages (from-to)402-416
Number of pages15
Issue number2
StatePublished - Feb 2009


  • Alzheimer's disease
  • Axonal damage signalling
  • Axonal dystrophy
  • Synapse dysfunction
  • TgCRND8


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