In the June 25, 2009, issue of Neuron, a paper added to the litany of ways in which A-beta oligomers contribute to the symptoms of Alzheimer's disease. They enhance long-term depression, a weakening in neural connections that is the physical way in which brain cells forget.
The anatomical calling cards of Alzheimer's disease are amyloid plaques, or aggregates of A-beta peptide. But a growing number of researchers believe that the real problem with plaques is not the plaques themselves, but that they provide a reservoir for A-beta oligomers - smaller aggregations of A-beta peptide that are soluble and can spread far and wide to do their damage.
In the Neuron paper, senior author Dennis Selkoe and his team showed that adding A-beta oligomers to brain slices - in the sorts of concentrations that might naturally be present in an aging brain - "quite strongly facilitates" long-term depression, a weakening of neural connections. Whether the effects identified in the paper are technically toxic "depends on your definition of toxicity," Selkoe told BioWorld Today. A-beta oligomers do not kill neurons outright, though in high concentrations they do ultimately damage them physically. And after all, forgetting is a normal, necessary and helpful part of brain function.
But in one way, that is precisely what makes the changes in neural communication that Selkoe and his colleagues described typical of Alzheimer's disease.
"I can hardly point to an event in the entire [disease] process that is truly unique to Alzheimer's," Selkoe said. Instead, what happens in Alzheimer's is "too much of a normal thing," he said.
Neurons communicate through electrical signals, and the connection between two neurons can be altered permanently if one neuron fires multiple times in a row. Whether such stimulation is able to permanently alter the connection, and whether an altered connection will be strengthened or weakened, depends on the strength and patterning of the pulses. In the most simple terms, strengthening of neural connections or long-term potentiation is thought to be the way in which neurons store memories, whereas a permanent weakening or long-term depression is a way for memories to be erased.
In their paper, Selkoe, who is co-director of the Center for Neurologic Diseases at Brigham and Women's Hospital, and his colleagues, from Harvard Medical School and University College Dublin, used isolated brain slices to test how neural transmission was altered by exposure to A-beta oligomers, and used a variety of receptor blockers to tease out the transmitter systems underlying the changes.
They found that A-beta increased the effectiveness of stimulation patterns that weaken neuronal connections, making it easier to induce long-term depression. That finding is complementary to earlier work that had shown that A-beta oligomers make it harder to strengthen neural connections.
Mechanistically, A-beta appears to increase glutamate concentrations in the synapse by hindering its recycling. When Selkoe and his colleagues added a glutamate scavenger to the brain slices before stimulation, regular long-term depression was not altered. But the increases in long-term depression due to A-beta were reversed by the scavenger, showing that the increased long-term depression results from increased levels of glutamate.
In their paper, Selkoe and his colleagues wrote that their findings "have both mechanistic and therapeutic implications for the initiation of hippocampal synaptic failure in AD and in more subtle forms of age-related A-beta accumulation."
Selkoe said that a specific lesson from the work is that A-beta oligomers could be targeted therapeutically. "If you could find a small molecule that coats the A-beta oligomer or prevents its binding to the cell membrane . . . chances are that you would get less loss of synapses, and therefore improved learning."
Elan Pharmaceuticals, of which Selkoe is a co-founder, currently is developing one candidate, as are others in the field.
More generally, Selkoe said, the work argues that an aggressive approach to early stage Alzheimer's will be necessary to make a dent in the disease, which is the most common neurodegenerative disorder and on the increase as the population ages.
Instead of focusing on what delivers the final blow to kill a cell, the focus should be on "what suddenly impairs the function of neurons, long before they die," Selkoe said.
"To treat Alzheimer's, you have to really nip it in the bud," he added.