Introduction

Despite the availability of a wide range of animal models of Alzheimer disease, none of them are able to fully recapitulate all the facets of the disease. Axonopathy is a case in point. Although there has been renewed interest in the link between axonal swellings and pathological hallmarks of AD, such as neurofibrillary tangles and Aβ aggregates, the majority of mouse models exhibit no gross axonal abnormalities. The recently described model from Thomas Bayer’s lab at Saarland University, Germany, is one exception. Thomas Bayer presented his data on axonopathy in a bigenic mouse model of AD on 29 November 2006.
 

Thomas Bayer led this Webinar on 29 November 2006.

View Video Recording

Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Background

Background Text
By Thomas Bayer

Transgenic mice have proven to be a valuable model system to study the pathological alterations in Alzheimer disease (AD). We studied APP expression, Aβ deposition, and axonal alterations in the brain and spinal cord of a bigenic transgenic mouse model expressing mutant APP751SL on a homozygous mutant (PS1M233T and PS1 L235P) PS1 knock-in background (named APP/PS1ki). These mice have been shown to develop amyloid plaques at 2 months of age with robust antecedent intraneuronal accumulation of Aβ peptides in hippocampal and cortical areas. Furthermore, they exhibit significant CA1/2 neuronal loss at 10 months of age (more than 50 percent), a pathological feature that has not been convincingly proven in most other APP transgenic mouse models (Casas et al., 2004).

Some neurodegenerative diseases including 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 focused on the issue of whether Aβ serves as a trigger for aberrant axonal transport in the pathophysiology of AD. We analyzed axonal neuropathology in the brain and spinal cord of the APP/PS1ki mouse model with abundant intraneuronal AβX-42 production and provide compelling evidence for axonal degeneration (see Wirths et al., 2006 and also ARF related news story). 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. Additionally, we have reported on age-dependent axonal degeneration in another bigenic APP751SL/PS1(M146L) transgenic mouse (Wirths et al., 2006). We conclude that the accumulation of intraneuronal Aβ-amyloid peptides might induce axonal transport deficits, which lead to axonal degradation and subsequent neuron loss in AD.

Comments

No Available Comments

Make a Comment

To make a comment you must login or register.

References

News Citations

1. Is Motor Neuron Axonopathy behind Movement Problems in Alzheimer Disease? 13 Mar 2006

Webinar Citations

1. Webinar: Axonopathy in Mouse Models of AD 30 Nov 2006

Paper Citations

1. Casas C, Sergeant N, Itier JM, Blanchard V, Wirths O, van der Kolk N, Vingtdeux V, van de Steeg E, Ret G, Canton T, Drobecq H, Clark A, Bonici B, Delacourte A, Benavides J, Schmitz C, Tremp G, Bayer TA, Benoit P, Pradier L. Massive CA1/2 neuronal loss with intraneuronal and N-terminal truncated Abeta42 accumulation in a novel Alzheimer transgenic model. Am J Pathol. 2004 Oct;165(4):1289-300. PubMed.
2. Wirths O, Weis J, Kayed R, Saido TC, Bayer TA. Age-dependent axonal degeneration in an Alzheimer mouse model. Neurobiol Aging. 2007 Nov;28(11):1689-99. PubMed.
3. Wirths O, Weis J, Szczygielski J, Multhaup G, Bayer TA. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease. Acta Neuropathol. 2006 Apr;111(4):312-9. PubMed.

Further Reading