Cellular mechanisms for amyloid beta-protein activation of rat cholinergicbasal 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 hallmark s of Alzheimer's disease oh the mechanism of A beta neurotoxicity is unknow n, (AD). Although the mechanism of A beta neurotoxicity is unknown, these c holinergic neurons display a selective vulnerability when exposed to this p eptide. In this study, application of A beta (25-35) or A beta (1-40) to ac utely dissociated rat neurons from the basal forebrain nucleus diagonal ban d of Broca (DBB), caused a decrease in whole cell voltage-activated current s in a majority of cells. This reduction in whole cell currents occurs thro ugh a modulation of a suite of potassium conductances including calcium-act ivated potassium (I-C), the delayed rectifier (I-K), and transient outward potassium (I-A) conductances, but not calcium or sodium currents. Under cur rent-clamp conditions, A beta evoked an increase in excitability and a loss of accommodation in cholinergic. DBB neurons. Using sin.-le-cell RT-PCR te chnique, we determined that A beta actions were specific to cholinergic, bu t not GABAergic DBB neurons. A beta effects on whole cell currents were occ luded in the presence of membrane-permeable protein tyrosine kinase inhibit ors, genistein and tyrphostin B-44. Our data indicate that the A beta actio ns on specific potassium conductances are modulated through a protein tyros ine kinase pathway and that these effects are selective to cholinergic but not GABAergic cells. These observations provide a cellular basis for the se lectivity of A beta neurotoxicity toward cholinergic basal forebrain neuron s that are at the epicenter of AD pathology.