Beta -amyloid-(1-42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival Is not compromised.
Cognitive impairment is a major feature of Alzheimer's disease and is accompanied by beta-amyloid (Abeta) deposition. Transgenic animal models that overexpress Abeta exhibit learning and memory impairments, but neuronal degeneration is not a consistent characteristic. We report that levels of Abeta-(1-42), which do not compromise the survival of cortical neurons, may indeed interfere with functions critical for neuronal plasticity. Pretreatment with Abeta-(1-42), at sublethal concentrations, resulted in a suppression of cAMP-response element-binding protein (CREB) phosphorylation, induced by exposure to either 30 mm KCl or 10 microm N-methyl-d-aspartate. The effects of Abeta-(1-42) seem to involve mechanisms unrelated to degenerative changes, since Abeta-(25-35), a toxic fragment of Abeta, at sublethal concentrations did not interfere with activity-dependent CREB phosphorylation. Furthermore, caspase inhibitors failed to counteract the Abeta-(1-42)-evoked suppression of CREB activation. Abeta-(1-42) also interfered with events downstream of activated CREB. The Abeta-(1-42) treatment suppressed the activation of the cAMP response element-containing brain-derived neurotrophic factor (BDNF) exon III promoter and the expression of BDNF exon IIII mRNA induced by neuronal depolarization. In view of the critical role of CREB and BDNF in neuronal plasticity, including learning and memory, the observations indicate a novel pathway through which Abeta may interfere with neuronal functions and contribute to cognitive deficit in Alzheimer's disease before the stage of massive neuronal degeneration.
University of California, Irvine Institute for Brain Aging and Dementia, Irvine, California 92697-4540, USA. tongl@uci.edu
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D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000502:physiology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004622:Embryo, Mammalian; D005091:Exons; D005786:Gene Expression Regulation / Q000187:drug effects; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D011189:Potassium Chloride / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
D000590:Amino Acid Chloromethyl Ketones; D016229:Amyloid beta-Peptides; D019208:Brain-Derived Neurotrophic Factor; D017362:Cyclic AMP Response Element-Binding Protein; D015853:Cysteine Proteinase Inhibitors; D010446:Peptide Fragments; D012333:RNA, Messenger; C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D016202:N-Methylaspartate; D011189:Potassium Chloride