Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory.
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.
Taylor
Chanel J
CJ
Department of Psychology, University of Otago, Box 56, Dunedin, New Zealand.
Ireland
David R
DR
Ballagh
Irene
I
Bourne
Katie
K
Marechal
Nicola M
NM
Turner
Paul R
PR
Bilkey
David K
DK
Tate
Warren P
WP
Abraham
Wickliffe C
WC
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism*; D006877:Hydroxamic Acids / Q000494:pharmacology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D008569:Memory Disorders / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D013028:Space Perception / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology
D016564:Amyloid beta-Protein Precursor; D000906:Antibodies; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; C092152:N-((2-(hydroxyaminocarbonyl)methyl)-4-methylpentanoyl)-3-(2'-naphthyl)alanylalanine, 2-aminoethylamide; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D018698:Glutamic Acid; D053829:Amyloid Precursor Protein Secretases