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 E. coli (HypF-N), are also synaptotoxic. HypF-N oligomers were found to (i) colocalise 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 rise 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.

Amyloid-β oligomer synaptotoxicity is mimicked by oligomers of the model protein HypF-N / Francesca Tatini; Anna Maria Pugliese; Chiara Traini; Sandra Niccoli; Giovanna Maraula; Teresa Ed Dami; Benedetta Mannini; Tania Scartabelli; Felicita Pedata; Fiorella Casamenti; Fabrizio Chiti. - In: NEUROBIOLOGY OF AGING. - ISSN 0197-4580. - STAMPA. - 34:(2013), pp. 2100-2109. [10.1016/j.neurobiolaging.2013.03.020]

Amyloid-β oligomer synaptotoxicity is mimicked by oligomers of the model protein HypF-N

PUGLIESE, ANNA MARIA;TRAINI, CHIARA;PEDATA, FELICITA;CASAMENTI, FIORELLA;CHITI, FABRIZIO
2013

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 E. coli (HypF-N), are also synaptotoxic. HypF-N oligomers were found to (i) colocalise 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 rise 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.
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Francesca Tatini; Anna Maria Pugliese; Chiara Traini; Sandra Niccoli; Giovanna Maraula; Teresa Ed Dami; Benedetta Mannini; Tania Scartabelli; Felicita Pedata; Fiorella Casamenti; Fabrizio Chiti
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2158/807671
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