The Smoking Gun in Alzheimer's Disease Found
GLENVIEW, Ill., Aug. 18 /PRNewswire/ -- Researchers at Northwestern, USC and Acumen Pharmaceuticals have discovered for the first time in humans the neurotoxic peptide assemblies believed to be responsible for Alzheimer's disease. This is an important step towards developing effective drugs that delay Alzheimer's progression, prevent its onset, and potentially restore cognitive function in patients with memory-related disorders. The findings will be published online by the Proceedings of the National Academy of Sciences during the week of Aug. 18.
William L. Klein led the research team with important collaboration from Grant A. Krafft and Caleb E. Finch; all three are founders of Acumen Pharmaceuticals. "This is a very important step in solving the Alzheimer's puzzle," said William Klein, a member of Acumen's Scientific Advisory Board and Professor of Neurobiology at Northwestern University. "In 1998, we discovered ADDLs -- new, highly toxic assemblies of the amyloid beta peptide. We also demonstrated that synthetically made ADDLs disrupt the key learning and memory functions of neurons. These are the clinical symptoms of Alzheimer's disease. Until today, it was a theory supported by test tube experiments. Now, we can say it's real." The report shows that 70 times more small, soluble, aggregated peptides called "amyloid beta-derived diffusible ligands" (ADDLs, pronounced "addles") is found in Alzheimer's brain tissue compared to levels in normal elderly individuals. The report also shows that when ADDLs attack neurons, they are found not just anywhere -- they are found bound very selectively to receptors on nerve cells associated with learning and memory.
The clinical data strongly support a recent theory put forth by Acumen's founders that ADDLs are the cause of Alzheimer's disease. "We now have a clearly defined molecular mechanism to explain memory loss and nerve cell degeneration in Alzheimer's disease," said Caleb Finch, also a member of Acumen's Scientific Advisory Board and Professor of Gerontology at USC. "ADDLs are formed, they bind selectively to receptors associated with memory, and the synapses lose their ability to store information. Over time, continuous ADDL assault causes neurons to die, permanently breaking the connections that store our long-term memories. These are the late stages of Alzheimer's disease." Synapses are points of communication where neurons exchange information in the brain. "Now we've shown that ADDLs are present in Alzheimer's-affected patients and are a clinically valid part of Alzheimer's pathology."
Although they assemble from the same peptide building block, ADDLs differ significantly from individual amyloid peptides and from amyloid fibrils (known as plaques), a diagnostic hallmark of AD. ADDLs in human brain consist mostly of assemblies of 12 or 24 individual amyloid beta peptides, each 42 amino acids long. Alone each single peptide is benign. When assembled, ADDLs are soluble and diffuse throughout the brain until the bind to vulnerable synapses. Individual peptides do not. Fibrils on the other hand, are significantly larger and lack many of the physical properties of ADDLs, acting as immobile waste deposits.
The presence of ADDLs in Alzheimer's brain helps explain the poor correlation between plaques and neurological deficits. Other important studies have demonstrated that memory failure in mouse models can be reversed when treated with amyloid beta antibodies but without ANY reduction in plaque or total amounts of amyloid beta peptide. These antibodies appear to restore memory because they neutralize ADDLs.
"Now, it's our job to get anti-ADDLs drugs into the clinic," said Grant Krafft, Acumen's Chief Scientific Officer. "We believe that preventing the formation of ADDLs, or preventing them from binding to nerve cell receptors is the right therapeutic approach. Acumen has antibodies that bind selectively to ADDLs, and we are pursuing drugs candidates that prevent ADDLs from assembling and binding to receptors. Anti-ADDL approaches are likely to provide a safe and effective way to stop disease progression and restore cognitive function in patients with memory deficits."
Northwestern and USC hold joint patents on ADDL composition, and on methods and uses of anti-ADDL compounds for treatment of memory-related disorders. This intellectual property has been licensed to Acumen Pharmaceuticals, Inc., based in Glenview, Ill. Clinical trials are approximately two 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, all from Northwestern University. The National Institutes of Health, the Boothroyd, Feiger and French foundations, and Institute for the Study of Aging, and Acumen Pharmaceuticals supported the research. Acumen Pharmaceuticals is a private biotech company, engaged in developing the first effective therapeutics and diagnostics for Alzheimer's disease and other memory-related disorders. See www.acumenpharm.com for more information. |
