Cellular mechanisms for amyloid β-protein activation of rat cholinergic basal forebrain neurons

The deposition of amyloid beta -protein (A beta) in the brain and the loss of cholinergic neurons in the basal forebrain are two pathological hallmarks of Alzheimer's disease oh the mechanism of A beta neurotoxicity is unknown, (AD). Although the mechanism of A beta neurotoxicity is unknown, these cholinergic neurons display a selective vulnerability when exposed to this peptide. In this study, application of A beta (25-35) or A beta (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 (I-C), the delayed rectifier (I-K), and transient outward potassium (I-A) conductances, but not calcium or sodium currents. Under current-clamp conditions, A beta evoked an increase in excitability and a loss of accommodation in cholinergic. DBB neurons. Using sin.-le-cell RT-PCR technique, we determined that A beta actions were specific to cholinergic, but not GABAergic DBB neurons. A beta 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 beta 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 beta neurotoxicity toward cholinergic basal forebrain neurons that are at the epicenter of AD pathology.