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.
Wirths O, Weis J, Szczygielski J, Multhaup G, Bayer TA. Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer’s disease. Acta Neuropathologica. March 7, 2006. Online First edition. Abstract
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