Researchers have uncovered evidence that the first time that neurotoxic peptide assemblies known as ADDLs are responsible for Alzheimer's disease in humans. The findings were published online by the Proceedings of the National Academy of Sciences on August 18.
"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," according to Acumen Pharmaceuticals, whose scientists were involved in the project alongside researchers at Northwestern University and the University of Southern California. The company is expecting to start clinical trials of ADDL-targeting agents win the next two years.
"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 … Until today, it was a theory supported by test tube experiments. Now, we can say it's real."
The study reveals that 70 times more of the small, soluble, aggregated peptides (amyloid beta-derived diffusible ligands or ADDLs) are found in Alzheimer's brain tissue compared to levels in normal elderly individuals. Using antibodies against amyloid beta peptide, the researchers demonstrated that ADDLs accumulate on cells in the cerebral cortex that govern learning and memory.
"We now have a clearly defined molecular mechanism to explain memory loss and nerve cell degeneration in Alzheimer's disease," said Caleb Finch, another 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," he suggested.
Although they assemble from the same peptide building block, ADDLs differ significantly from amyloid peptides and from amyloid fibrils (known as plaques), which are a diagnostic hallmark of Alzheimer's disease.
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, according to Acumen. However, when assembled, ADDLs are soluble and diffuse throughout the brain until they bind to vulnerable synapses. Individual peptides do not behave in this way, it said, while fibrils are significantly larger and lack many of the physical properties of ADDLs, acting as immobile waste deposits.
Acumen also contends that the memory failure in mouse models that can be reversed when treated with amyloid beta antibodies - but without a reduction in plaque or total amounts of amyloid beta peptide - come about because the antibodies neutralise ADDLs.
"Now, it's our job to get anti-ADDLs drugs into the clinic," said Grant Krafft, Acumen's chief scientific officer. Acumen has already identified antibodies that bind selectively to ADDLs, and is also pursuing drugs candidates that prevent ADDLs from assembling and binding to receptors.