title: Aβ inhibition of ionic conductance in mouse basal forebrain neurons is dependent upon the cellular prion protein PrPC.
abstract: Current therapies for Alzheimer's disease (AD) address a loss of cholinergic neurons, while accumulation of neurotoxic amyloid β (Aβ) peptide assemblies is thought central to molecular pathogenesis. Overlaps may exist between prionopathies and AD wherein Aβ oligomers bind to the cellular prion protein PrP(C) and inhibit synaptic plasticity in the hippocampus (Laurén et al., 2009). Here we applied oligomeric Aβ 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, Aβ₁₋₄₂ 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 (I(K)), the transient outward (I(A)), and the iberiotoxin-sensitive (calcium-activated potassium, I(C)) currents. Inhibition was not seen with Aβ₄₂₋₁ peptide, while Aβ₁₋₄₂-induced responses were reduced by application of anti-PrP antibody, attenuated in cells from Prnp⁰/⁺ hemizygotes, and absent in Prnp⁰/⁰ homozygotes. Similarly, amyloidogenic amylin peptide depressed DBB whole-cell currents in DBB cells from wt mice, but not Prnp⁰/⁰ homozygotes. While prior studies give broad support for a neuroprotective function for PrP(C), our data define a latent pro-pathogenic role in the presence of amyloid assemblies.
authors.affiliation: Department of Medicine-Neurology, University of Alberta, Edmonton, Alberta T6G2S2, Canada.
authors.forename: Kwai
authors.initials: K
authors.lastname: Alier
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.forename: David
authors.initials: D
authors.lastname: Westaway
authors.forename: Jack H
authors.initials: JH
authors.lastname: Jhamandas
mesh_terms: D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects / Q000235:genetics; D002118:Calcium / Q000378:metabolism; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects* / Q000235:genetics; D058228:Islet Amyloid Polypeptide / Q000494:pharmacology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques / Q000379:methods; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D016548:Prosencephalon / Q000166:cytology*
chemical_list: D016229:Amyloid beta-Peptides; D058228:Islet Amyloid Polypeptide; D010446:Peptide Fragments; D010455:Peptides; D015221:Potassium Channels; D011328:Prions; C075222:amyloid beta-protein (1-42); C064719:iberiotoxin; D002118:Calcium
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