December 21, 2004
Study Shows Toxic Proteins Affect Memory
EVANSTON, Ill.—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, PhD, professor of neurobiology and physiology, found that toxic proteins, called “amyloid Ã-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 November 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,” Dr. Klein said. “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 Dr. Klein and 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 with 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, demonstrated the same pattern of binding to synapses on specific neurons. What is striking about ADDLs, Dr. Klein said, is that they disrupt the neurons’ ability to communicate with each other without killing the neurons.
“Human and animal studies have pointed to synaptic damage and loss as the key determinant of the severity of memory loss, correlating better than either neuronal loss or the presence of plaques,” said Pascale N. Lacor, PhD, lead author on the paper and a research assistant professor of neurobiology and physiology.
“ADDLs selectively target a synaptic population,” Dr. Lacor said, “and at these sites they modify the expression of essential memory-related molecules. We saw subtle changes happening to the gene Arc after only five minutes of exposure to ADDLs, and those changes were sustained for an unexpectedly long time. Our next step is to understand why ADDLed synapses have trouble staying connected and storing memories.”
ADDLS are small, soluble, aggregated proteins. The clinical data strongly support a recent theory in which ADDLs accumulate at the beginning of Alzheimer’s disease and block memory function by a process predicted to be reversible.
Although both are a form of amyloid beta, ADDLs and their properties differ significantly from the amyloid fibrils (known as plaques) that are a diagnostic hallmark of Alzheimer’s. ADDLs found in human brains, mostly 12 or 24 amyloid beta proteins clumped together, are tiny and undetectable in conventional neuropathology; fibrils are much larger. While fibrils are immobile toxic waste dumps, ADDLs are soluble and diffuse between brain cells until they find vulnerable synapses. (Single pieces of amyloid beta protein in the brain is normal.)
Dr. Klein, Grant A. Krafft, PhD, formerly at Northwestern University’s Feinberg School of Medicine and now chief scientific officer at Acumen Pharmaceuticals, Inc., and Caleb E. Finch, PhD, professor of biological sciences and gerontology at the University of Southern California, reported the discovery of ADDLs in 1998. Drs. Krafft and Finch are co-authors on the Journal of Neuroscience paper. Northwestern and USC hold joint patents on the composition and use of ADDLs in neurodisorders.
The patent rights have been licensed to Acumen Pharmaceuticals, based in Glenview, Ill., for the development of drugs that treat Alzheimer’s disease and other memory-related disorders.
In addition to Drs. Klein, Lacor, Krafft, and Finch, other authors on the paper are Maria C. Buniel, Lei Chang, Sara J. Fernandez, Yuesong Gong, Kirsten L. Viola, Mary P. Lambert, Pauline T. Velasco, and Eileen H. Bigio, from Northwestern University.
The research was supported by the National Institutes of Health; Boothroyd, Feiger and French Foundations; Institute for the Study of Aging; and Illinois Department of Public Health Alzheimer’s Disease Research Fund.
(Dr. Klein is a founder of Acumen Pharmaceuticals, Inc. and serves as a member of its scientific advisory board. In January Merck & Co., Inc. entered into a research collaboration and license agreement with Acumen to investigate ADDLs as a drug target.)