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Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease

Oliver Wirths1, Joachim Weis, Jacek Szczygielski

  • 1Department of Psychiatry, Division of Neurobiology, Saarland University, Building 90, 66421, Homburg, Saar, Germany.

Acta Neuropathologica
|March 8, 2006
PubMed

Insights

Alzheimer's disease (AD) involves axonopathy, a nerve fiber degeneration. This study shows elevated intracellular amyloid-beta in transgenic mice causes axonal spheroids and myelin ovoids, supporting the amyloid hypothesis in AD pathogenesis.

Area of Science:

  • Neuroscience
  • Pathology
  • Genetics

Background:

  • Axonopathy is common in neurodegenerative diseases but understudied in Alzheimer's disease (AD).
  • Motor deficits are frequently observed in AD patients, suggesting underlying axonal dysfunction.

Purpose of the Study:

  • To investigate axonopathy in a transgenic mouse model of Alzheimer's disease (AD) with elevated intracellular amyloid-beta (Abeta).
  • To determine if increased intracellular Abeta levels lead to specific axonal pathologies.

Main Methods:

  • Utilized transgenic mice overexpressing human mutant beta-amyloid precursor protein (APP(751SL)) and presenilin-1 (PS1(M146L)).
  • Examined spinal cords for age-dependent axonal alterations, including ubiquitin-positive axons, axonal spheroids, and myelin ovoids.
  • Assessed accumulation of APP, neurofilament, and ubiquitin within axonal swellings.

Main Results:

  • Observed age-dependent axonopathy in the spinal cord, including ubiquitin-positive axons and axonal spheroids.
  • Identified axonal spheroids containing APP, neurofilament, and ubiquitin, along with myelin ovoids indicating nerve fiber degeneration.
  • Detected early intraneuronal Abeta in motor neurons preceding plaque formation; neuritic plaques developed in an age-dependent manner.

Conclusions:

  • Elevated intracellular Abeta levels in the APP/PS1 transgenic model induce axonopathy characterized by axonal spheroids and myelin ovoids.
  • These axonal pathologies occur independently of Tau pathology, strengthening the amyloid cascade hypothesis in AD.
  • The findings highlight the significance of axonopathy in AD pathogenesis and support Abeta as a primary trigger.

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