Attack from Outer Space
Klein’s group took a similar experimental approach, treating highly differentiated cultures of hippocampal neurons with ADDLs/oligomers, but in this case it appears that the major toxic effects were initiated from without. First author Pascale Lacor and colleagues found that ADDLs bound exclusively to neurons that express NMDA-type glutamate receptors. Inhibitory GABA-ergic neurons failed to bind the protein oligomers, suggesting that Aβ has a particular grudge against NMDA neurons. They also found that ADDLs bound primarily to postsynaptic sites. Synaptosomes isolated from ADDL-treated neurons using ADDL antibodies contained postsynaptic density 95 and the NR1 and NR2A/B subunits of the NMDA receptor. They did not contain the presynaptic protein syntaxin.
ADDLs had a major effect on the plasticity and morphology of dendritic spines. Lacor and colleagues found that within three hours of ADDL treatment, levels of NR1 and NR2B had fallen by 78 and 70 percent, respectively. At 6 hours post-treatment, levels of the NMDA receptor-associated protein EphB2 had fallen by 60 percent. The findings are reminiscent of earlier work from Paul Greengard and Gunnar Gouras’s labs at Rockefeller University and Cornell University, respectively (see ARF related news story) and of work from Roberto Malinow’s lab at Cold Spring Harbor Laboratories, also in New York, showing that soluble Aβ can bring down AMPA-type glutamate receptors (see ARF related news story).
Lacor and colleagues found gross morphological changes, as well. The number of spines, as judged by the spine marker drebrin, fell by about half 24 hours after treatment, while their average length roughly doubled. “The change in spine appearance caused by ADDLs is especially interesting because the elongated shape resembles that of immature spines or of disease spines found in mental retardation and prionoses,” the authors wrote. A similar spine loss is emerging in other preparations, as well (see ARF Eibsee conference report). Intriguingly, Klein’s team found that the NMDA receptor blocker memantine, which has been approved for treatment of early AD, protected against ADDL-induced drebrin loss, suggesting that the drug may have pleiotropic effects.
Dial M for Membrane
And finally, there’s Aβ’s effect on lipids. Oxidation of lipids has long been considered a potential harbinger of problems in neurons, and 4-hydroxynonenal (HNE) in particular has been studied in the context of AD. This byproduct of lipid oxidation can cross-react with protein side chains and is elevated in AD (see ARF related news story). Oxidized lipids have also been shown to increase Aβ aggregation and Aβ to promote lipid oxidation, but it was not clear how the two were related. Now, Axelsen and colleagues report that HNE constitutes a missing link.
First author Ian Murray and colleagues report that Aβ stimulates production of HNE from synthetic lipid vesicles and that this reaction requires the presence of copper (see related live discussion on the role of Aβ/Cu in oxidation reactions). Murray and colleagues also found that Aβ can promote HNE formation in lipid extracts from human brain, suggesting that the chemical reactions may be physiologically relevant. They also report that HNE covalently modifies Aβ40 and Aβ42 on histidine side chains. These modified Aβs not only have a greater tendency to aggregate, but they also have an increased affinity for lipid membranes, indicating that they may produce even more HNE.—Tom Fagan.
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Lacor PN, Buniel MC, Furlow PW, Sanz Clemente A, Velasco PT, Wood M, Viola KL, Klein WL. A[beta] oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J. Neurosci. 2007 Jan 24;27:796-807. Abstract
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