Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice

Abstract

The pathology of Alzheimer's disease (AD) is comprised of extracellular amyloid plaques, intracellular tau tangles, dystrophic neurites and neurodegeneration. The mechanisms by which these various pathological features arise are under intense investigation. Here, expanding upon pilot gene expression studies, we have further analyzed the relationship between Na+/K+ ATPase and amyloid using APP+PS1 transgenic mice, a model that develops amyloid plaques and memory deficits in the absence of tangle formation and neuronal or synaptic loss. We report that in addition to decreased mRNA expression, there was decreased overall Na+/K+ ATPase enzyme activity in the amyloid-containing hippocampi of the APP+PS1 mice (although not in the amyloid-free cerebellum). In addition, dual immunolabeling revealed an absence of Na+/K+ ATPase staining in a zone surrounding congophilic plaques that was occupied by dystrophic neurites. We also demonstrate that cerebral Na+/K+ ATPase activity can be directly inhibited by high concentrations of soluble Aβ. The data suggest that the reductions in Na+/K+ ATPase activity in Alzheimer tissue may not be purely secondary to neuronal loss, but may results from direct effects of amyloid on this enzyme. This disruption of ion homeostasis and osmotic balance may interfere with normal electrotonic properties of dendrites, blocking intraneuronal signal processing, and contribute to neuritic dystrophia. These results suggest that therapies aimed at enhancing Na+/K+ ATPase activity in AD may improve symptoms and/or delay disease progression.

DOI: 10.1186/1471-2202-6-7

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@article{Dickey2004DysregulationON, title={Dysregulation of Na+/K+ ATPase by amyloid in APP+PS1 transgenic mice}, author={Chad A Dickey and Marcia N Gordon and Donna M . Wilcock and Donna Lorraine Herber and M. J. Freeman and David Gene Morgan}, journal={BMC Neuroscience}, year={2004}, volume={6}, pages={7 - 7} }