Although motor deficits such as a characteristically abnormal gait have been documented in Alzheimer disease (AD), their exact cause is unknown. Now a paper in the March 7 Acta Neuropathologica online hints at an explanation that may be worth further investigation. Researchers in Germany report widespread spinal cord axonopathy in a mouse model of AD. The damage extends to the white matter and motor neurons, raising the possibility that motor neuron deficits might be a facet of AD itself. More broadly, the study highlights a dearth of knowledge about axonal transport deficits in animal models and human AD.

Thomas Bayer and colleagues at Saarland University, Technical University of Aachen, and Free University of Berlin discovered the axonopathy when they examined spinal cords of mice that express mutant forms of human amyloid-β precursor protein (AβPP) and presenilin 1 (PS1). In these double transgenics, strong expression of the PS1 M146L and the AβPP Swedish/London mutant proteins contribute to rampant production and age-dependent accumulation of intraneuronal Aβ42. In contrast to some other mouse models of AD, amyloid plaques are readily apparent in the brain by the time these mice are 3 months old (see Wirths et al., 2002).

When joint first authors Oliver Wirths and Joachim Weis examined the spinal cords of these animals, they spotted dilatations, or spheroids, containing ubiquitin and APP in both the white and gray matter of the cord. While the plaques materialized—as in the brain—by 3 months of age, the spinal cord spheroids did not show up until about 8 months, becoming widespread by 13 months. Analyzing cord sections under the electron microscope, the authors found that the spheroids contained electron-dense organelles and cytoskeletal elements. Antibodies also detected a variety of neurofilament subunits.

The findings suggest that overproduction of Aβ can lead to axonopathy in motor neurons. A growing number of scientists is becoming interested in axonal transport deficits as a potential contributor to neurodegeneration (see, e.g., the 2004 and 2005 Enabling Technology Workshops, and John Trojanowski’s axonal transport hypothesis of neurodegenerative diseases). The topic drew further attention when tantalizing, if controversial, data appeared suggesting that motor neuron axonopathy might be an important feature of the disease. Last year, for example, Larry Goldstein’s group at the University of California, San Diego, reported that axonopathy is an early event in the brain of not only AβPP transgenic mice, but also AD patients (see Stokin et al., 2005). However, there is scant evidence for axonopathy in the spinal cord of AD patients, save for an early report that Aβ deposits are found there (see Ogomori et al., 1989). Earlier work from Fred van Leuven’s lab at the Katholieke Universiteit Leuven, Belgium reported axonopathy in the spinal cord of tau and ApoE mouse models of AD (see Spittaels et al., 1999 and Tesseur et al., 2000, respectively).

The question in the present study is whether the axonopathy observed by Wirths and colleagues in this mouse model is in any way analogous to what goes on in AD. Curiously, Flint Beal and colleagues at Cornell University, New York, have reported that in amyotrophic lateral sclerosis patients, Aβ is deposited in motor neurons of the lumbar region of the spinal cord (see Calingasan et al., 2005). This seems to suggest that Aβ can accumulate in spinal cord neurons even when produced at relatively normal levels.

On that note, other current work hints at further overlapping processes between these two otherwise distinct neurodegenerative diseases. AD neurologists use gait abnormalities as one of many indicators that a person may have AD, and an upcoming study in this month’s Annals of Neurology, by researchers at Columbia University College of Physicians and Surgeons in New York, reports that a third of a cohort of ALS patients developed cognitive impairment as their disease progressed (Rippon et al., 2006). To date, there is no consensus view of exactly how APP and tau figure in axonal transport deficits and axonopathy, but the latter could be at play across several different neurodegenerative diseases.—Tom Fagan


  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.


    . Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005 Feb 25;307(5713):1282-8. PubMed.

  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.


    . Overexpression of tau protein inhibits kinesin-dependent trafficking of vesicles, mitochondria, and endoplasmic reticulum: implications for Alzheimer's disease. J Cell Biol. 1998 Nov 2;143(3):777-94. PubMed.

    . Fast axonal transport misregulation and Alzheimer's disease. Neuromolecular Med. 2002;2(2):89-99. PubMed.

    . Alzheimer's presenilin 1 mutations impair kinesin-based axonal transport. J Neurosci. 2003 Jun 1;23(11):4499-508. PubMed.

    . Axonal transport defects: a common theme in neurodegenerative diseases. Acta Neuropathol. 2005 Jan;109(1):5-13. PubMed.

  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.


    . Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol. 1999 Dec;155(6):2153-65. PubMed.

    . Glycogen synthase kinase-3beta phosphorylates protein tau and rescues the axonopathy in the central nervous system of human four-repeat tau transgenic mice. J Biol Chem. 2000 Dec 29;275(52):41340-9. PubMed.

    . Expression of human apolipoprotein E4 in neurons causes hyperphosphorylation of protein tau in the brains of transgenic mice. Am J Pathol. 2000 Mar;156(3):951-64. PubMed.

    . Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am J Pathol. 2000 Nov;157(5):1495-510. PubMed.

    . Axonal transport, tau protein, and neurodegeneration in Alzheimer's disease. Neuromolecular Med. 2002;2(2):151-65. PubMed.

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Paper Citations

  1. . Intraneuronal APP/A beta trafficking and plaque formation in beta-amyloid precursor protein and presenilin-1 transgenic mice. Brain Pathol. 2002 Jul;12(3):275-86. PubMed.
  2. . Axonopathy and transport deficits early in the pathogenesis of Alzheimer's disease. Science. 2005 Feb 25;307(5713):1282-8. PubMed.
  3. . Beta-protein amyloid is widely distributed in the central nervous system of patients with Alzheimer's disease. Am J Pathol. 1989 Feb;134(2):243-51. PubMed.
  4. . Prominent axonopathy in the brain and spinal cord of transgenic mice overexpressing four-repeat human tau protein. Am J Pathol. 1999 Dec;155(6):2153-65. PubMed.
  5. . Prominent axonopathy and disruption of axonal transport in transgenic mice expressing human apolipoprotein E4 in neurons of brain and spinal cord. Am J Pathol. 2000 Nov;157(5):1495-510. PubMed.
  6. . Beta-amyloid 42 accumulation in the lumbar spinal cord motor neurons of amyotrophic lateral sclerosis patients. Neurobiol Dis. 2005 Jun-Jul;19(1-2):340-7. PubMed.

Other Citations

  1. 2004

Further Reading

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Primary Papers

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