title: Intraneuronal Aβ accumulation induces hippocampal neuron hyperexcitability through A-type K(+) current inhibition mediated by activation of caspases and GSK-3.
abstract: Amyloid β-protein (Aβ) pathologies have been linked to dysfunction of excitability in neurons of the hippocampal circuit, but the molecular mechanisms underlying this process are still poorly understood. Here, we applied whole-cell patch-clamp electrophysiology to primary hippocampal neurons and show that intracellular Aβ42 delivery leads to increased spike discharge and action potential broadening through downregulation of A-type K(+) currents. Pharmacologic studies showed that caspases and glycogen synthase kinase 3 (GSK-3) activation are required for these Aβ42-induced effects. Extracellular perfusion and subsequent internalization of Aβ42 increase spike discharge and promote GSK-3-dependent phosphorylation of the Kv4.2 α-subunit, a molecular determinant of A-type K(+) currents, at Ser-616. In acute hippocampal slices derived from an adult triple-transgenic Alzheimer's mouse model, characterized by endogenous intracellular accumulation of Aβ42, CA1 pyramidal neurons exhibit hyperexcitability accompanied by increased phosphorylation of Kv4.2 at Ser-616. Collectively, these data suggest that intraneuronal Aβ42 accumulation leads to an intracellular cascade culminating into caspases activation and GSK-3-dependent phosphorylation of Kv4.2 channels. These findings provide new insights into the toxic mechanisms triggered by intracellular Aβ42 and offer potentially new therapeutic targets for Alzheimer's disease treatment.
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy.
authors.forename: Federico
authors.initials: F
authors.lastname: Scala
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Fusco
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Ripoli
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Piacentini
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy.
authors.forename: Domenica Donatella
authors.initials: DD
authors.lastname: Li Puma
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Spinelli
authors.affiliation: Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, USA.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Laezza
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy. Electronic address: grassi@rm.unicatt.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Grassi
authors.affiliation: Institute of Human Physiology, Medical School, Università Cattolica, Rome, Italy. Electronic address: dascenzo@rm.unicatt.it.
authors.forename: Marcello
authors.initials: M
authors.lastname: D'Ascenzo
mesh_terms: D000200:Action Potentials / Q000235:genetics; D000544:Alzheimer Disease / Q000209:etiology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D020169:Caspases / Q000502:physiology*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D055724:Electrophysiological Phenomena / Q000235:genetics*; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism / Q000503:physiopathology*; D066298:In Vitro Techniques; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000378:metabolism / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism / Q000633:toxicity*; D010766:Phosphorylation / Q000235:genetics; D051672:Shal Potassium Channels / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D051672:Shal Potassium Channels; C075222:amyloid beta-protein (1-42); D038362:Glycogen Synthase Kinase 3; D020169:Caspases
keywords: A-type K(+) current; Alzheimer's disease; Amyloid-β protein; Caspase; GSK-3; Hippocampal neurons; Intrinsic excitability; KV4.2