title: Centaurin-α1-Ras-Elk-1 signaling at mitochondria mediates β-amyloid-induced synaptic dysfunction.
abstract: Alzheimer's disease is thought to be caused by β-amyloid peptide (Aβ)-dependent synaptic dysfunction. However, the signaling pathways connecting Aβ and synaptic dysfunction remain elusive. Here we report that Aβ transiently increases the expression level of centaurin-α1 (CentA1) in neurons, which induces a Ras-dependent association of Elk-1 with mitochondria, leading to mitochondrial and synaptic dysfunction in organotypic hippocampal slices of rats. Downregulation of the CentA1-Ras-Elk-1 pathway restored normal mitochondrial activity, spine structural plasticity, spine density, and the amplitude and frequency of miniature EPSCs in Aβ-treated neurons, whereas upregulation of the pathway was sufficient to decrease spine density. Elevations of CentA1 and association of Elk-1 with mitochondria were also observed in transgenic mice overexpressing a human mutant form of amyloid precursor protein. Therefore, the CentA1-Ras-Elk-1 signaling pathway acts on mitochondria to regulate dendritic spine density and synaptic plasticity in response to Aβ in hippocampal neurons, providing new pharmacological targets for Alzheimer's disease.
authors.affiliation: Department of Neurobiology and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Erzsebet M
authors.initials: EM
authors.lastname: Szatmari
authors.forename: Ana F
authors.initials: AF
authors.lastname: Oliveira
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Sumner
authors.forename: Ryohei
authors.initials: R
authors.lastname: Yasuda
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000378:metabolism / Q000473:pathology; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C491062:Adap1 protein, rat; D016229:Amyloid beta-Peptides; C494113:Elk1 protein, mouse; C494114:Elk1 protein, rat; D020690:GTPase-Activating Proteins; D009419:Nerve Tissue Proteins; D050807:ets-Domain Protein Elk-1; D018631:ras Proteins