title: Effects of different amyloid β-protein analogues on synaptic function.
abstract: Perisynaptic accumulations of amyloid β-protein (Aβ) play a critical role in the synaptic dysfunction underlying the cognitive impairment observed in Alzheimer's disease. The methionine residue at position 35 (Met35) in Aβ is highly subject to oxidation in Alzheimer's disease brains. In hippocampal brain slices we found that long-term potentiation at CA3-CA1 synapses was significantly inhibited by wild type Aβ42 in which Met35 is reduced, but not by Aβ42 harboring Met35 sulfoxide. Similar differences were observed when basal synaptic transmission was investigated in autaptic hippocampal neurons. The significant decreases in excitatory postsynaptic current amplitude, vesicle release probability and miniature excitatory postsynaptic current frequency caused by 20-minute exposure to wild type Aβ42 were not observed after exposure to Aβ42 harboring Met35 sulfoxide. With longer (24-hour) Aβ treatments, this early impairment of the presynaptic terminal function extended to involve the postsynaptic side as well. The Met35 oxidation also affected Aβ42 negative impact on dendritic spine density and expression of pre- and postsynaptic proteins (synaptophysin and postsynaptic density protein-95). Our findings suggest that oxidation of Met35 is critical for molecular, structural, and functional determinants of Aβ42 synaptotoxicity.
authors.affiliation: Institute of Human Physiology, Università Cattolica, Rome, Italy.
authors.forename: Cristian
authors.initials: C
authors.lastname: Ripoli
authors.forename: Roberto
authors.initials: R
authors.lastname: Piacentini
authors.forename: Elisa
authors.initials: E
authors.lastname: Riccardi
authors.forename: Lucia
authors.initials: L
authors.lastname: Leone
authors.forename: Domenica D
authors.initials: DD
authors.lastname: Li Puma
authors.forename: Gal
authors.initials: G
authors.lastname: Bitan
authors.forename: Claudio
authors.initials: C
authors.lastname: Grassi
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002478:Cells, Cultured; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)