β-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 (A beta) deposition. Transgenic animal models that overexpress A beta exhibit learning and memory impairments, but neuronal degeneration is not a consistent characteristic. We report that levels of A beta-(1- 42), which do not compromise the survival of cortical neurons, may indeed interfere with functions critical for neuronal plasticity. Pretreatment with A beta-(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 muM N-methyl-D-aspartate. The effects of A beta-(1-42) seem to involve mechanisms unrelated to degenerative changes, since AP-(25-35), a toxic fragment of A beta, at sublethal concentrations did not interfere with activity-dependent CREB phosphorylation. Furthermore, caspase inhibitors failed to counteract the A beta-(1-42)-evoked suppression of CREB activation. A beta-(1-42) also interfered with events downstream of activated CREB, The A beta-(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 A beta may interfere with neuronal functions and contribute to cognitive deficit in Alzheimer's disease before the stage of massive neuronal degeneration.