Cellular mechanisms for amyloid -protein activation of rat cholinergic basal
forebrain neurons.
Jhamandas, Jack H., Caroline Cho, Balvinder Jassar, Kim Harris, David MacTavish and
Jacob Easaw.
Division of Neurology, Department of Medicine, University of Alberta, Edmonton,
Alberta, Canada T6G 2S2
APStracts 8:0227J, 2001.
The deposition of amyloid -protein (A ) in the brain and the loss of cholinergic neurons
in the basal forebrain are two pathological hallmarks of Alzheimer's disease (AD).
Although the mechanism of A neurotoxicity is unknown, these cholinergic neurons
display a selective vulnerability when exposed to this peptide. In this study, application
of A 25-35 or A 1-40 to acutely dissociated rat neurons from the basal forebrain
nucleus diagonal band of Broca (DBB), caused a decrease in whole cell voltage-activated
currents in a majority of cells. This reduction in whole-cell currents occurs through a
modulation of a suite of potassium conductances including calcium-activated potassium
(IC), the delayed rectifier (IK) and transient outward potassium (IA) conductances, but
not calcium or sodium currents. Under current clamp conditions, A evoked an increase
in excitability and a loss of accommodation in cholinergic DBB neurons. Using single
cell RT-PCR technique, we determined that A actions were specific to cholinergic, but
not GABAergic DBB neurons. A effects on whole cell currents were occluded in the
presence of membrane permeable protein tyrosine kinase inhibitors, genistein and
tyrphostin B-44. Our data indicate that the A actions on specific potassium conductances
are modulated through a protein tyrosine kinase pathway and that these effects are
selective to cholinergic but not GABAergic cells. These observations provide a cellular
basis for the selectivity of A neurotoxicity towards cholinergic basal forebrain neurons
which are at the epicentre of AD pathology.
Received 7 February 2001; accepted in final form 24 May 2001
APS Manuscript Number J105-1.
Article publication pending Am J Physiol
ISSN 1080-4757 Copyright 2001 The American Physiological Society.
Published in APStracts on 31 July 2001