title: Amyloid-β oligomer synaptotoxicity is mimicked by oligomers of the model protein HypF-N.
abstract: Protein misfolded oligomers are thought to be the primary pathogenic species in many protein deposition diseases. Oligomers by the amyloid-β peptide play a central role in Alzheimer's disease pathogenesis, being implicated in synaptic dysfunction. Here we show that the oligomers formed by a protein that has no link with human disease, namely the N-terminal domain of HypF from Escherichia coli (HypF-N), are also synaptotoxic. HypF-N oligomers were found to (i) colocalize with post-synaptic densities in primary rat hippocampal neurons; (ii) induce impairment of long-term potentiation in rat hippocampal slices; and (iii) impair spatial learning of rats in the Morris Water Maze test. By contrast, the native protein and control nontoxic oligomers had none of such effects. These results raise the importance of using HypF-N oligomers as a valid tool to investigate the pathogenesis of Alzheimer's disease, with advantages over other systems for their stability, reproducibility, and costs. The results also suggest that, in the context of a compromised protein homeostasis resulting from aggregation of the amyloid β peptide, a number of oligomeric species sharing common synaptotoxic activity can arise and cooperate in the pathogenesis of the disease.
authors.affiliation: Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Tatini
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Pugliese
authors.forename: Chiara
authors.initials: C
authors.lastname: Traini
authors.forename: Sandra
authors.initials: S
authors.lastname: Niccoli
authors.forename: Giovanna
authors.initials: G
authors.lastname: Maraula
authors.forename: Teresa
authors.initials: T
authors.lastname: Ed Dami
authors.forename: Benedetta
authors.initials: B
authors.lastname: Mannini
authors.forename: Tania
authors.initials: T
authors.lastname: Scartabelli
authors.forename: Felicita
authors.initials: F
authors.lastname: Pedata
authors.forename: Fiorella
authors.initials: F
authors.lastname: Casamenti
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Chiti
mesh_terms: D000371:Agglutination; D000544:Alzheimer Disease / Q000235:genetics*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000633:toxicity*; D000818:Animals; D019878:Carboxyl and Carbamoyl Transferases / Q000737:chemistry* / Q000633:toxicity*; D002478:Cells, Cultured; D029968:Escherichia coli Proteins / Q000737:chemistry* / Q000633:toxicity*; D006624:Hippocampus / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D017774:Long-Term Potentiation / Q000187:drug effects; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments; D057907:Post-Synaptic Density / Q000187:drug effects; D055503:Protein Multimerization; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects*
chemical_list: D016229:Amyloid beta-Peptides; D029968:Escherichia coli Proteins; D010446:Peptide Fragments; D019878:Carboxyl and Carbamoyl Transferases; C504838:hypF protein, E coli