Premium
O2‐02–08: Dimeric cross‐linked Abeta species disrupt and oxidize membranes
Author(s) -
Moir Robert D.,
Soscia Stephanie J.,
Tucker Stephanie,
Tanzi Rudolph E.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.320
Subject(s) - membrane , chemistry , lipid bilayer , biochemistry , lipid peroxidation , amyloid (mycology) , microbiology and biotechnology , biophysics , membrane protein , amyloid beta , biology , oxidative stress , peptide , inorganic chemistry
underlying this process is not known. Methods: We used rat hippocampal slice preparations and human cortical neurons in culture to investigate the mechanism of synaptic targeting of A O. Results: Here we show that the specific targeting of soluble A species to synapses is dramatically regulated by synaptic activity. We observed increased synaptic localization of A oligomers after neuronal stimulation with KCl or glutamate in both rat hippocampal organotypic slices and human cortical neuronal cultures. Conversely, a reduction in A O synaptic localization was observed after synaptic silencing with TTX. Synaptic activity also promoted A oligomerization specifically at synaptic terminals after addition of pure monomeric A . One possibility is that elevations in the concentration of metal ions in the cleft as a result of synaptic activity recruit A O to the synaptic area, given the high affinity of A for metal ions, especially Cu and Zn . Consistent with this hypothesis, there was a marked reduction in A O synaptic localization when cells were pretreated with the chelator clioquinol. A O were not internalized in recycled synaptic vesicles after stimulation, and remained at the cell surface. Most A O at synaptic sites colocalized with NR2B subunits of the NMDA receptor and NMDA antagonists blocked A O localization at synapses, suggesting that excitatory synapses are major sites of A O accumulation. Oligomeric immunoreactivity was also detected in AD brains using three different conformation-specific antibodies. Oligomeric structures of different size were closely associated with synaptic markers, consistent with biochemical data indicating the presence of heterogeneous oligomeric conformations in AD brain. Conclusions: Thus, synaptic activity plays a major role in A O synaptic targeting, and A O-ion metal interactions and specific NMDA receptor sub-types appear to be directly involved in this process.