. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease. Acta Neuropathol. 2006 Apr;111(4):312-9. PubMed.


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  1. 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.

    View all comments by Jürgen Götz
  2. 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.

    View all comments by Jorge Busciglio
  3. The paper by Oliver Wirths in the group of Thomas Bayer is another instance connecting amyloid and axonal problems, manifested by the axonal spheroids in spinal cord of mutant APPxPS1 mice. It is clear that the spheroids develop secondarily to intraneuronal Aβ and plaques. Since early axonal dysfunction was not assessed—or absent—it is difficult to judge these observations in terms of "cause, correlation, or consequence." Nevertheless, even when secondary to the real insult, axonal problems will contribute to neuronal dysfunction and even to tangle formation (Terwel et al., 2002).

    Reference in the Wirths paper, and in Tom Fagan's Alzforum story, to our transgenic mice expressing either tau-4R or ApoE4 in neurons driven by the thy1 gene promoter, prompts me to recap and comment on the underlying mechanisms (Spittaels et al., 1999, 2000; Tesseur et al., 2000a,b).

    First, we observed very similar axonal problems in both types of our mice, that is, axonal spheroids containing all sorts of "transported" materials, followed by Wallerian degeneration of the axons distal to the spheroids, and finally muscle weakening and wasting. Evidently, all this was accompanied by motor problems, setting in at a very early age in homozygous tau-4R mice (at weaning) and later in life in heterozygous tau-4R mice as in thy1-ApoE4 mice (Spittaels et al.,1999; Tesseur et al., 2000). The pathology was largely confined to motor neurons in brainstem and spinal cord, never really extending into forebrain or hippocampus, despite equally strong expression of either transgene in all these brain regions.

    We concluded then (and still do) that, since mouse motor neurons are extremely sensitive to insults, this must include overexpression of transgenes driven by the thy1-gene promoter. Nevertheless, we did not observe any axonal problems in our mutant APP and PS1 single and double Tg mice driven both by the identical thy1 gene promoter to equal high levels! Nor did we see it in transgenic strains expressing Cdk5/p35 or GSK3β using exactly the same promoter, actually the opposite: GSK3β rescued the axonopathy of tau-4R mice (Spittaels et al., 2000).

    Clearly, the promoter does not explain the entire story and the major part of the pathological problem stems from the actual transgene, that is, tau-4R and neuronal ApoE4. Both gave rise to hyperphosphorylation of tau and of neurofilaments, indications of cytoskeletal problems—not so mutant APP, alone or in combination with mutant PS1!

    We have analyzed spinal cords from only a limited number of old to very old APP and APPxPS1 mice, but have now seen brain from several hundred of such mice, and have not observed axonal spheroids. We have unpublished data on APPxPS1xTau-4R triple Tg mice, which die early in life (3-6 months), but have no more spheroids than the parental tau-4R mice (Van Dorpe et al., unpublished data).

    Since the double-mutant APP-SL transgene in the Wirths paper is driven by the thy1- gene promoter, and the mutant PS1 gene by the HMG-CoAR gene promoter, and both to very high levels, we suspect that the combined action is sufficient to stress motor neurons considerably. In addition, the very high Aβ levels in the double Tg mice (274-fold higher than in single APP mice) must be a major contributing factor. In this respect, it remains amazing that no indications for phosphorylated tau were observed, telling us again that there is much more to the amyloid-tau link than the actual concentration of Aβ, be it intracellular or extracellular!

    Is this relevant for the human AD pathology? Perhaps, perhaps not. Only further refined experimental models will tell—building on what we learned from studies as reported and commented on here.

    View all comments by Ilse Dewachter