b-Amyloid increases dendritic Ca
2+
influx by inhibiting the A-type
K
+
current in hippocampal CA1 pyramidal neurons
Chu Chen
*
Neuroscience Center, School of Medicine, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
Received 23 October 2005
Available online 14 November 2005
Abstract
Accumulation of the b-amyloid peptide (Ab) is a primary event in the pathogenesis of AlzheimerÕs disease (AD). However, the mech-
anisms by which Ab 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 Ab-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 Ab (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
Ca
2+
influx. These results suggest that the persistent inhibition of the A-type K
+
current resulting from deposition of Ab in dendritic
arborization will induce a sustained increase in dendritic Ca
2+
influx and lead to loss of Ca
2+
homeostasis. This may be a component
of the events that cause synaptic failure and initiate neuronal degenerative processes in the hippocampus.
Ó 2005 Elsevier Inc. All rights reserved.
Keywords: Voltage-gated potassium channels; Patch-clamp; Calcium imaging; Dendrites; Hippocampus; b-Amyloid; AlzheimerÕs disease; Calcium
homeostasis; Membrane excitability
AlzheimerÕs disease (AD) is a neurodegenerative disease
characterized by progressive deterioration of cognitive
function and loss of memory in association with wide-
spread neuronal death. There is ample evidence indicating
that accumulation of the b-amyloid peptide (Ab) is a pri-
mary event in the pathogenesis of AD, but the mechanisms
by which Ab mediates neurotoxicity and initiates the
degenerative processes of AD are still not clear.
A key to understanding the action of Ab in AD is to
determine how this protein affects the neuronal networks
in which memories are stored, thereby causing dementia
[1]. Synapses in the hippocampus are the key components
of these neuronal networks. A deficit in function and struc-
ture of synapses may be a primary problem in the early
stages of AD [1,2].Ab-induced synaptic failure may initial-
ly arise from a sustained increase in intracellular Ca
2+
,
and/or loss of Ca
2+
homeostasis in dendritic spines, spe-
cialized structures that are involved in synaptic signaling
[3–5]. Abnormally large increases in intracellular Ca
2+
have
been observed in neurons during exposure to Ab: these
increases may result from Ab action on L-type Ca
2+
chan-
nels, or on an a7 nicotinic acetylcholine receptor, and pos-
sibly through an Ab protein formed Ca
2+
-permeable,
Zn
2+
-sensitive channel [3,4,6–12]. However, the mechanism
by which Ab-induced loss of Ca
2+
homeostasis leads to a
synaptic failure has yet to be elucidated. Recent evidence
shows that a transient A-type K
+
current distribution is
non-uniform in dendrites of hippocampal CA1 pyramidal
neurons and that there is a linear increase in A-type K
+
channel current density with an increase in the distance
from soma to distal dendrites [13]. This K
+
channel in
the dendrites has been shown to exert a powerful regulato-
ry control over the dendritic signal propagation and overall
neuronal excitability that contributes to synaptic plasticity
[13,14].Ab has been reported to inhibit the transient A-
type K
+
channel current in cultured hippocampal neurons,
0006-291X/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.bbrc.2005.10.169
*
Fax: +1 504 599 0891.
E-mail address: cchen@lsuhsc.edu.
www.elsevier.com/locate/ybbrc
Biochemical and Biophysical Research Communications 338 (2005) 1913–1919
BBRC