Endogenous secreted amyloid precursor protein-α regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory
| Autor: | David K. Bilkey, David Ireland, Nicola M. Marechal, Warren P. Tate, Chanel J. Taylor, Wickliffe C. Abraham, Paul R. Turner, Katie Bourne, Irene Ballagh |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Male
Recombinant Fusion Proteins Glutamic Acid Endogeny AMPA receptor Hippocampal formation Hydroxamic Acids Hippocampus Receptors N-Methyl-D-Aspartate Synaptic Transmission Antibodies lcsh:RC321-571 Rats Sprague-Dawley Amyloid beta-Protein Precursor Alzheimer Disease Memory Amyloid precursor protein Animals Dentate gyrus Enzyme Inhibitors lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Secreted APPβ Memory Disorders Secreted APPα Dose-Response Relationship Drug biology Chemistry Long-term potentiation Dipeptides NMDA receptor Rats Cell biology Neurology Space Perception Synaptic plasticity biology.protein Amyloid Precursor Protein Secretases Neuroscience |
| Zdroj: | Neurobiology of Disease, Vol 31, Iss 2, Pp 250-260 (2008) |
| Popis: | Secreted amyloid precursor protein-alpha (sAPP alpha) levels are reduced during the pathogenesis of Alzheimer's disease, but the significance of this for neural function is not well understood. Here, we show that intrahippocampal infusion of antibodies targeted to endogenous sAPP alpha reduced long-term potentiation (LTP) in the dentate gyrus of adult rats by approximately 50%. Conversely, infusion of recombinant sAPP alpha dose-dependently increased LTP and facilitated in vitro tetanically evoked NMDA receptor-mediated currents. Pharmacological inhibition of alpha-secretase and other a-disintegrin-and-metalloproteases by TAPI-1 reduced both LTP and tetanus-evoked NMDA receptor-mediated currents in dentate granule cells. Both effects were prevented by co-application of exogenous recombinant sAPP alpha. Similarly, spatial memory was inhibited by intrahippocampal TAPI-1, an effect that was prevented by co-application of recombinant sAPP alpha. Together these findings indicate that endogenous sAPP alpha is a key contributor to synaptic plasticity and spatial memory. Its reduced production in Alzheimer's disease may thus contribute to the clinical memory deficits. |
| Databáze: | OpenAIRE |
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