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The University of Queensland
The paper by Wirths and coworkers underscores the importance of axonopathy In Alzheimer disease. Their data obtained in APP/PS1 transgenic mice nicely extend previous findings in related animal models. Specifically, the authors refer to the findings of axonopathy and transport deficits in tau transgenic mice (as shown by several groups) and APP transgenic mice as reported by Larry Goldstein's group (Stokin et al., 2005). However, the Goldstein group also describes in that paper an axonopathy in AD brain, which they interestingly enough find for early, but not late Braak stages. The overall picture emerging from all of these studies is that key players in AD, such as APP and tau (possibly in a synergistic manner) perturb axonal transport early on in AD.
Stokin GB, Lillo C, Falzone TL, Brusch RG, Rockenstein E, Mount SL, Raman R, Davies P, Masliah E, Williams DS, Goldstein LS. Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005 Feb 25;307(5713):1282-8. PubMed.View all comments by Jürgen Götz
University of California, Irvine
This interesting paper provides clear evidence that amyloid pathology in the double transgenic model causes axonopathy. The results suggest that intracellular Aβ accumulation in double transgenic mice may lead to trafficking defects in axons. While the results are compelling in the double transgenic, no such alterations are observed in single transgenic animals. Furthermore, amyloid pathology in spinal cord and axonopathy appear to be variable features that are not always present in AD patients. As the authors suggest, subtler alterations in signal transduction pathways, leading to misregulation of axonal transport and/or cytoskeletal disruption, may lead to motor deficits not only in AD, but also in other neurodegenerative conditions as well (Ebneth et al., 1998; Morfini et al., 2002; Pigino et al., 2003; Roy et al., 2005). Further studies will be required to determine if intracellular Aβ accumulation leads to motor dysfunction in AD.
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Morfini G, Pigino G, Beffert U, Busciglio J, Brady ST. Fast axonal transport misregulation and Alzheimer's disease. Neuromolecular Med. 2002;2(2):89-99. PubMed.
Pigino G, Morfini G, Pelsman A, Mattson MP, Brady ST, Busciglio J. Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci. 2003 Jun 1;23(11):4499-508. PubMed.
Roy S, Zhang B, Lee VM, Trojanowski JQ. Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol. 2005 Jan;109(1):5-13. PubMed.View all comments by Jorge Busciglio