beta-Amyloid-(1-42) impairs activity-dependent cAMP-response element-binding protein signaling in neurons at concentrations in which cell survival isnot compromised

Cognitive impairment is a major feature of Alzheimer's disease and is accom panied by beta -amyloid (A beta) deposition. Transgenic animal models that overexpress A beta exhibit learning and memory impairments, but neuronal de generation is not a consistent characteristic. We report that levels of A b eta-(1- 42), which do not compromise the survival of cortical neurons, may indeed interfere with functions critical for neuronal plasticity. Pretreatm ent with A beta-(1-42), at sublethal concentrations, resulted in a suppress ion of cAMP-response element-binding protein (CREB) phosphorylation, induce d by exposure to either 30 mM KCl or 10 muM N-methyl-D-aspartate. The effec ts of A beta-(1-42) seem to involve mechanisms unrelated to degenerative ch anges, since AP-(25-35), a toxic fragment of A beta, at sublethal concentra tions did not interfere with activity-dependent CREB phosphorylation. Furth ermore, caspase inhibitors failed to counteract the A beta-(1-42)-evoked su ppression of CREB activation. A beta-(1-42) also interfered with events dow nstream of activated CREB, The A beta-(1-42) treatment suppressed the activ ation of the cAMP response element-containing brain-derived neurotrophic fa ctor (BDNF) exon III promoter and the expression of BDNF exon IIII mRNA ind uced by neuronal depolarization. In view of the critical role of CREB and B DNF 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.