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Modulation of Na +,K + pumping and neurotransmitter uptake by ß-amyloid

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Gu,  Q.B.
Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Max Planck Society;
Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China;

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Zhao,  J.X.
Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Max Planck Society;
Shanghai Institute of Biochemistry and Cell Biology, Shanghai, China;

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Schwarz,  Wolfgang
Department of Biophysical Chemistry, Max Planck Institute of Biophysics, Max Planck Society;

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Citation

Gu, Q., Zhao, J., Fei, J., & Schwarz, W. (2004). Modulation of Na +,K + pumping and neurotransmitter uptake by ß-amyloid. Neuroscience, 126, 61-67. doi:10.1016/j.neuroscience.2004.03.022.


Cite as: https://hdl.handle.net/11858/00-001M-0000-0024-DA9C-F
Abstract
Micromolar concentrations of β-amyloid (Aβ), a 40/42-amino-acid-long proteolytic fragment (Aβ1–40/42) of the amyloid precursor protein, was shown previously to play a crucial role in pathogenesis of Alzheimer's disease. We used the Xenopus oocyte expression system to investigate specific effects of micromolar concentrations of Aβ1–42 on the neurotransmitter transporters for γ-aminobutyric acid (GABA), GAT1, and for the excitatory amino acid glutamate, EAAC1, which are driven by the transmembrane Na+ gradient that is regulated by the Na+,K+-ATPase. Brief treatment with Aβ1–42, up to 80 min, leads to a significant inhibition of ion translocation by the Na+,K+-ATPase (30–40%); also glutamate uptake is inhibited (20%) while GABA uptake is not affected. Since reduced glutamate uptake will result in elevated, neurotoxic concentrations of extracellular glutamate, we investigated the effects of Aβ1–42 and the smaller fragments, Aβ12–28 and Aβ25–35, on EAAC1 in more detail. Prolonged incubation in 1 μM Aβ1–42 leads to further, strong inhibition of glutamate uptake and EAAC1-mediated current (after 4 h inhibition amounts to more than 80%). Aβ12–28 is less effective with 50% inhibition after 4 h of incubation at 20 μM. Aβ1–42 and Aβ12–28 affect EAAC1-mediated current to a similar extent as the rate of glutamate uptake. The effects on EAAC1-mediated current are irreversible if Aβ were applied for longer time periods. Peptides directly microinjected into the oocyte are ineffective suggesting that the observed effect were mediated by extracellular proteins. Aβ25–35 hardly affects EAAC1-mediated current or glutamate uptake.

The results demonstrate that Aβ specifically inhibits the Na+,K+ pump and EAAC1. The domain between amino acids 12 and 28 of Aβ seems to play a crucial role for inhibition of EAAC1. The inhibition of EAAC1 by neurotoxic, elevated extracellular glutamate levels may contribute to Alzheimer's pathogenesis.