An understanding of this key molecular link in the progression of Alzheimer's 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. Help for individuals with pre-Alzheimer's memory failure (mild cognitive impairment) also is envisioned. The findings will be published online by the Proceedings of the National Academy of Sciences during the week of Aug. 18.
The research team, led by William L. Klein, professor of neurobiology and physiology, found up to 70 times more small, soluble aggregated proteins called "amyloid b-derived diffusible ligands" (ADDLs, pronounced "addles") in the brain tissue of individuals with Alzheimer's disease compared to that of normal individuals.
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. ADDLs have the ability to attack the memory-building activity of synapses, points of communication where neurons exchange information, without killing neurons.
"Researchers for more than a decade thought it was big molecules, the 'amyloid fibrils,' that caused memory problems, but we think the real culprits are extremely small molecules, what we call ADDLs," said Klein, who is a member of Northwestern's Cognitive Neurology and Alzheimer's Disease Center. "Now we've shown that ADDLs are present in humans and are a clinically valid part of Alzheimer's pathology. If we can develop drugs that target and neutralize these neurotoxins, it might be possible to not only slow down memory loss, but to actually reverse it, to bring memory function back to normal."
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, 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.)
"The difference between ADDLs and fibrils is like comparing four eggs, over easy, to an enormous omelet that could feed the entire Chicago Bears team," said Klein. ""You start with eggs, but the final product taste, texture and size are all different."
The existence of ADDLs may help explain the poor correlation between plaques and neurological deficits. Studies by other researchers have shown a reversal of memory failure in mouse models treated with amyloid beta antibodies -- but without any reduction in plaque. The antibodies appear to restore memory because they neutralize ADDLs, which Klein's group has found in mouse models with Alzheimer's as well as in human brains with Alzheimer's.
Klein's research team recently began a study funded by the National Institutes of Health to continue investigating ADDLs in humans and further characterize these molecules. In addition to Alzheimer's disease, ADDL-like molecules could be the cause of other degenerative diseases.
Klein also is working with researchers at Northwestern's Institute for Nanotechnology on clinical diagnostics capable of detecting ADDLs in blood or cerebral spinal fluid. Currently diagnosis of Alzheimer's is based primarily on a battery of psychological tests.
"Now that ADDLs have been discovered in humans we would like to develop effective diagnostics and that means employing nanotechnology," said Klein. "That's because ADDLs are present in very low concentrations, and nanotechnology has the potential to provide the ultra-sensitive assays needed for the clinic."
Klein, Grant A. Krafft, formerly at Northwestern University Medical School and now chief scientific officer at Acumen Pharmaceuticals, Inc., and Caleb E. Finch, professor of biological sciences and gerontology at the University of Southern California, reported the discovery of ADDLs in 1998. Krafft and Finch are co-authors on the PNAS 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. Clinical trials could be two or three years away.
In addition to Klein, Krafft and Finch, other authors on the paper are Yuesong Gong (lead author), Lei Chang, Kirsten L. Viola, Pascale N. Lacor and Mary P. Lambert, from Northwestern University.
The research was supported by the National Institutes of Health, the Boothroyd, Feiger and French foundations, and the Institute for the Study of Aging.