Researchers at Northwestern University have discovered a molecular mechanism — a tiny protein attacking nerve cells — that could explain why the brain damage in early Alzheimer’s disease results in memory loss and not other symptoms such as loss of balance or tremors.

The research team, led by William L. Klein, professor of neurobiology and physiology, found that toxic proteins, called “amyloid ß-derived diffusible ligands” (ADDLs, pronounced “addles”), from the brain tissue of individuals with Alzheimer’s disease specifically attack and disrupt synapses, the nerve cell sites responsible for information processing and memory formation.



These results, which show that only particular neurons and synapses are targeted by the neurotoxins, were published Nov. 10 in the Journal of Neuroscience. An understanding of how ADDLs disrupt synapses without killing neurons could lead to the development of new therapeutic drugs capable of reversing memory loss in patients who are treated early, in addition to preventing or delaying the disease. “Memory starts at synapses, so it was probable that Alzheimer’s disease would be a synapse failure,” said Klein. “Our work, which shows that ADDLs bind with great specificity to synapses, is the first demonstration of that.



“Why is the damage so specific to memory? First, ADDLs bind to some synapses and not others — a very specific attack. Second, at the vulnerable synapses there is a gene linked to memory that is normally expressed. When ADDLs attack those synapses they disrupt the normal expression of that gene, resulting in memory loss.” Over-expression of that gene, called Arc, has been linked to dysfunctional learning in earlier studies of memory.



Last year Klein and his colleagues were the first to discover and report the presence of ADDLs in humans. They found up to 70 times more of the toxic proteins in the brain tissue of individuals with Alzheimer’s disease compared to that of normal individuals.



In the current study, the research team used both ADDLs obtained from human brain tissue and ADDLs synthesized in the laboratory. Experiments showed that all the ADDLs, regardless of origin, showed the same pattern of binding to synapses on specific neurons. What is striking about ADDLs, said Klein, is that they disrupt the neurons’ ability to communicate with each other without killing the neurons.



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