Age-dependent axonal degeneration in an Alzheimer mouse model

Oliver Wirths, Joachim Weis, Rakez Kayed, Takaomi C. Saido, Thomas A. Bayer

Research output: Contribution to journalArticle

91 Scopus citations

Abstract

Some neurodegenerative diseases including Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS) exhibit prominent defects in axonal transport. These defects can manifest as axonal swellings or spheroids, which correspond to axonal enlargements and aberrant accumulation of axonal cargoes, cytoskeletal proteins and lipids. Recently, a controversial scientific debate focussed on the issue whether Aβ serves as a trigger for aberrant axonal transport in the pathophysiology of AD. Prominent axonopathy has been shown to be induced by overexpression of proteins involved in several neurodegenerative diseases. Neurofilament, apolipoprotein E, Niemann-Pick protein and Tau transgenic mice with axonal trafficking deficits have been reported. Furthermore, motor deficits are frequently observed in patients with AD, which has been attributed to the typical tauopathy in post-mortem brain tissue. In the present report, we analyzed axonal neuropathology in the brain and spinal cord of a transgenic mouse model with abundant intraneuronal Aβ42 production and provide compelling evidence for axonal degeneration. The APP/PS1ki mice showed characteristic axonal swellings, spheroids, axonal demyelination and ovoids, which are myelin remnants of degenerated nerve fibers in an age-dependent manner. Abundant accumulation of intraneuronal N-modified Aβ, Thioflavin S-positive material and ubiquitin was found within the somatodendritic compartment of neurons. We conclude that the intraneuronal accumulation of Aβ-amyloid peptides is followed by axonal degeneration, and thus might be a causative factor for the axonal changes seen in AD.

Original languageEnglish (US)
Pages (from-to)1689-1699
Number of pages11
JournalNeurobiology of aging
Volume28
Issue number11
DOIs
StatePublished - Nov 1 2007
Externally publishedYes

Keywords

  • Alzheimer
  • Amyloid
  • Axonal degeneration
  • Axonal transport
  • Axonopathy
  • Intraneuronal Aβ
  • Transgenic mice

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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