beta-Amyloid increases dendritic Ca2+ influx by inhibiting the A-type K+ current in hippocampal CA1 pyramidal neurons.
Accumulation of the beta-amyloid peptide (Abeta) is a primary event in the pathogenesis of Alzheimer's disease (AD). However, the mechanisms by which Abeta 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 Abeta-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 Abeta (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 Abeta in dendritic arborization will induce a sustained increase in dendritic Ca2+ 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.
Chen
Chu
C
Neuroscience Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
D000200:Action Potentials / Q000187:drug effects; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D003712:Dendrites / Q000187:drug effects* / Q000378:metabolism; D006624:Hippocampus / Q000502:physiology*; D066298:In Vitro Techniques; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology*; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects* / Q000502:physiology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology*; D051381:Rats
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D024642:Potassium Channels, Voltage-Gated; C075222:amyloid beta-protein (1-42); D002118:Calcium