title: Suppression of a neocortical potassium channel activity by intracellular amyloid-β and its rescue with Homer1a.
abstract: It is proposed that intracellular amyloid-β (Aβ), before extracellular plaque formation, triggers cognitive deficits in Alzheimer disease (AD). Here we report how intracellular Aβ affects neuronal properties. This was done by injecting Aβ protein into rat and mouse neocortical pyramidal cells through whole-cell patch pipettes and by using 3xTg AD model mice, in which intracellular Aβ is accumulated innately. In rats, intracellular application of a mixed Aβ(1-42) preparation containing both oligomers and monomers, but not a monomeric preparation of Aβ(1-40), broadened spike width and augmented Ca(2+) influx via voltage-dependent Ca(2+) channels in neocortical neurons. Both effects were mimicked and occluded by charybdotoxin, a blocker of large-conductance Ca(2+)-activated K(+) (BK) channels, and blocked by isopimaric acid, a BK channel opener. Surprisingly, augmented Ca(2+) influx was caused by elongated spike duration, but not attributable to direct Ca(2+) channel modulation by Aβ(1-42). The Aβ(1-42)-induced spike broadening was blocked by electroconvulsive shock (ECS), which we previously showed to facilitate BK channel opening via expression of the scaffold protein Homer1a. In young 3xTg and wild mice, we confirmed spike broadening by Aβ(1-42), which was again mimicked and occluded by charybdotoxin and blocked by ECS. In Homer1a knock-out mice, ECS failed to block the Aβ(1-42) effect. Single-channel recording on BK channels supported these results. These findings suggest that the suppression of BK channels by intracellular Aβ(1-42) is a possible key mechanism for early dysfunction in the AD brain, which may be counteracted by activity-dependent expression of Homer1a.
authors.affiliation: Department of Physiology, Kanazawa Medical University, Ishikawa 920-0293, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Ueta
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.forename: Ryo
authors.initials: R
authors.lastname: Yamamoto
authors.forename: Naoko
authors.initials: N
authors.lastname: Inoue
authors.forename: Kaoru
authors.initials: K
authors.lastname: Inokuchi
authors.forename: Atsu
authors.initials: A
authors.lastname: Aiba
authors.forename: Hideto
authors.initials: H
authors.lastname: Yonekura
authors.forename: Nobuo
authors.initials: N
authors.lastname: Kato
mesh_terms: D015761:4-Aminopyridine / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000235:genetics; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002264:Carboxylic Acids / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D018999:Charybdotoxin / Q000494:pharmacology; D004597:Electroshock / Q000379:methods; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000072233:Homer Scaffolding Proteins; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019579:Neocortex / Q000166:cytology*; D009433:Neural Inhibition / Q000187:drug effects* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009553:Nimodipine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010616:Phenanthrenes / Q000494:pharmacology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D053764:Presenilin-1 / Q000235:genetics; D051381:Rats; D016875:tau Proteins / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D002121:Calcium Channel Blockers; D002264:Carboxylic Acids; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D000072233:Homer Scaffolding Proteins; D007211:Indoles; D010446:Peptide Fragments; D010616:Phenanthrenes; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D018999:Charybdotoxin; C115138:isopimaric acid; D009553:Nimodipine; D015761:4-Aminopyridine; D002118:Calcium; C000543:cyclopiazonic acid