β-amyloid increases dendritic Ca2+ influx by inhibiting the A-type K+ current in hippocampal CA1 pyramidal neurons

Accumulation of the beta-amyloid peptide (A beta) is a primary event in the pathogenesis of Alzheimer's disease (AD). However, the mechanisms by which A beta mediates neurotoxicity and initiates the degenerative processes of AD are still not clear. Recent evidence shows that voltage-gated K+ channels may be involved in A beta-induced neurodegenerative processes. In particular, a transient A-type K+ current, with a linear increase in its density with distance from soma to distal dendrites in hippocampal CA1 pyramidal neurons, has been shown to contribute to dendritic membrane excitability. Here, I report that A beta (1-42) inhibits the dendritic A-type K+ current in hippocampal CA1 pyramidal neurons, and this inhibition causes increases in back-propagating dendritic action potential amplitude and associated Ca2+ influx. These results suggest that the persistent inhibition of the A-type K+ current resulting from deposition of AD in dendritic arborization will induce a sustained increase in dendritic Ca (2+) influx and lead to loss of Ca2+ homeostasis. This may be a component of the events that cause synaptic failure and initiate neuronal degenerative processes in the hippocampus. (c) 2005 Elsevier Inc. All rights reserved.