In three posters on Wednesday here at the annual Neuroscience meeting, William Klein’s laboratory extended their earlier presentation (see related news story) to add new pieces to the puzzle of the amyloid cascade hypothesis. One study indicates a steep elevation of the neurotoxic ligands in AD brain.
ADDLs, or Aβ oligomers, are notoriously difficult to detect in animals. Yuesong Gong presented data showing that soluble, nondenaturing extracts of AD brain tissue contained molecules that matched synthetic ADDLs with respect to size, isoelectric point, ligand specificity, and cross-reactivity. On average, these molecules were 1,200 percent more abundant in AD patients than in age-matched controls, with individual subjects elevated as much as 70-fold, the authors write.
Klein noted that the presence of oligomers in the brain is not well-recognized despite their recently verified role in interfering with LTP and the recognition that they are the putative target of therapeutic antibodies that reverse cognitive decline in mice models. "These are the hidden toxins, the missing links in the Alzheimer’s cascade," he said.
Pascale Lacor showed data that suggest a possible mechanism for how ADDLs might interfere with synaptic plasticity. Using immunofluorescent staining for synaptophysin, PSD-95, and spinophilin, the lab illustrated that ADDLs bind to receptors at postsynaptic terminals and subtly alter the structure of the terminals, including increasing the size of synaptic boutons. "ADDLs cause the synapses to show a little explosive growth, and this probably interferes with information storage," says Klein. For more on synaptic changes in AD, see related news story and related news story.
In a third poster, Lei Chang described an immunoassay which the lab developed to screen for molecules that inhibit ADDL formation. After screening several beta cyclodextrin-based libraries, the group identified one that was effective in blocking ADDL formation and toxicity at micromolar doses. They are now working to refine the compounds.
"The implication is that the way to help people with AD is to get rid of these molecules," said Klein. He believes oligomers present a better target for therapeutics and antibodies than do fibrils or plaques, not only because the impact of these soluble ligands is associated with synapse interference, but also because of the inflammatory reaction seen with the vaccine therapy developed so far. "If you have the antibodies bind to soluble molecules, you can avoid that inflammation," said Klein. To this end, Klein’s team has generated antibodies against ADDLs that target their assembled forms. The challenge ahead is to find antibodies that bind more specifically to ADDLs, but not to fibrils, in the hope of affecting a discrete pathway.—By guest writer Brenda Patoine.
Brenda Patoine is a science writer in Lagrangeville, New York, who writes for BrainWork and other publications.
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