Uptake and pathogenic effects of amyloid beta peptide 1-42 are enhanced by integrin antagonists and blocked by NMDA receptor antagonists.
Many synapses contain two types of receptors - integrins and N-methyl-D-aspartate (NMDA) receptors - that have been implicated in peptide internalization. The present studies tested if either class is involved in the uptake of the 42-residue form of amyloid beta peptide (Abeta1-42), an event hypothesized to be of importance in the development of Alzheimer's disease. Cultured hippocampal slices were exposed to Abeta1-42 for 6 days in the presence or absence of soluble Gly-Arg-Gly-Asp-Ser-Pro, a peptide antagonist of Arg-Gly-Asp (RGD)-binding integrins, or the disintegrin echistatin. Abeta uptake, as assessed with immunocytochemistry, occurred in 42% of the slices incubated with Abeta peptide alone but in more than 80% of the slices co-treated with integrin antagonists. Uptake was also found in a broader range of hippocampal subfields in RGD-treated slices. Increased sequestration was accompanied by two characteristics of early stage Alzheimer's disease: elevated concentrations of cathepsin D immunoreactivity and activation of microglia. The selective NMDA receptor antagonist D-(-)-2-amino-5-phosphonovalerate completely blocked internalization of Abeta, up-regulation of cathepsin D, and activation of microglia. Our results identify two classes of receptors that cooperatively regulate the internalization of Abeta1-42 and support the hypothesis that characteristic pathologies of Alzheimer's disease occur once critical intraneuronal Abeta concentrations are reached.
Bi
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X
Psychiatry and Human Behavior, 101 Theory, Suite 250, University of California at Irvine, 92697, USA. xbi@uci.edu
Gall
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CM
Zhou
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Lynch
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D015763:2-Amino-5-phosphonovalerate / Q000494:pharmacology; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000009:adverse effects* / Q000378:metabolism*; D000818:Animals; D002402:Cathepsin D / Q000378:metabolism; D046508:Culture Techniques; D006624:Hippocampus / Q000378:metabolism*; D007150:Immunohistochemistry; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism; D009842:Oligopeptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000009:adverse effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D016023:Integrins; D009842:Oligopeptides; D010446:Peptide Fragments; D016194:Receptors, N-Methyl-D-Aspartate; C075222:amyloid beta-protein (1-42); C101396:glycyl-arginyl-alanyl-aspartyl-seryl-proline; D015763:2-Amino-5-phosphonovalerate; C058161:glycyl-arginyl-glycyl-aspartyl-seryl-proline; D002402:Cathepsin D