TY - JOUR
T1 - Effects of different amyloid β-protein analogues on synaptic function
AU - Ripoli, Cristian
AU - Piacentini, Roberto
AU - Riccardi, Elisa
AU - Leone, Lucia
AU - Li Puma, Domenica Donatella
AU - Bitan, Gal
AU - Grassi, Claudio
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Amyloid-b protein
KW - Dentritic spines
KW - Long-term potentiation
KW - Synaptic transmission
KW - Amyloid-b protein
KW - Dentritic spines
KW - Long-term potentiation
KW - Synaptic transmission
UR - http://hdl.handle.net/10807/40099
U2 - 10.1016/j.neurobiolaging.2012.06.027
DO - 10.1016/j.neurobiolaging.2012.06.027
M3 - Article
SN - 0197-4580
VL - 34
SP - 1032
EP - 1044
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -