Aβ Inhibition of Ionic Conductance in Mouse Basal Forebrain Neurons Is Dependent upon the Cellular Prion Protein PrPC

Current therapies for Alzheimer's disease (AD) address a loss of cholinergic neurons, while accumulation of neurotoxic amyloid beta(A beta) peptide assemblies is thought central to molecular pathogenesis. Overlaps may exist between prionopathies and AD wherein A beta oligomers bind to the cellular prion protein PrPC and inhibit synaptic plasticity in the hippocampus (Lauren et al., 2009). Here we applied oligomeric A beta to neurons with different PrP (Prnp) gene dosage. Whole-cell recordings were obtained from dissociated neurons of the diagonal band of Broca (DBB), a cholinergic basal forebrain nucleus. In wild-type (wt) mice, A beta(1-42) evoked a concentration-dependent reduction of whole-cell outward currents in a voltage range between -30 and +30 mV; reduction occurred through a combined modulation of a suite of potassium conductances including the delayed rectifier (IK), the transient outward (I-A), and the iberiotoxin-sensitive (calcium-activated potassium, I-C) currents. Inhibition was not seen with A beta(42-1) peptide, while A beta(1-42)-induced responses were reduced by application of anti-PrP antibody, attenuated in cells from Prnp(0/+) hemizygotes, and absent in Prnp(0/0) homozygotes. Similarly, amyloidogenic amylin peptide depressed DBB whole-cell currents in DBB cells from wt mice, but not Prnp(0/0) homozygotes. While prior studies give broad support for a neuroprotective function for PrPC, our data define a latent pro-pathogenic role in the presence of amyloid assemblies.