Bethesda, MD – Scientists have identified a new, longer species of amyloid β-peptide that has the potential to be a new target for the treatment of Alzheimer’s disease.
The research appears as the "Paper of the Week" in the December 3 issue of the Journal of Biological Chemistry, an American Society for Biochemistry and Molecular Biology journal.
One of the characteristic features of Alzheimer’s disease is the deposition of amyloid β-peptides in the brain. These amyloid β-peptides are derived from a large amyloid precursor protein through a series of cleavage events. Under normal conditions, cleavage first by α-secretase and then by γ-secretase results in a soluble ectodomain, a short peptide called p3, and an intracellular C-terminal domain, none of which are amyloidogenic. Alternatively, amyloid precursor protein can be processed by the enzymes β-secretase and γ-secretase to produce a soluble ectodomain along with the full-length amyloidogenic amyloid β-peptide and the intracellular C-terminal domain.
Although amyloid precursor protein is found in many cells, its normal biological function is not well understood. "It has been suggested that amyloid precursor protein may function as a receptor or growth factor precursor," notes Dr. Xuemin Xu of The University of Tennessee. "Recent studies also suggest that the intracellular C-terminal domain of the amyloid precursor protein may function as a transcription factor."
While the exact pathogenic role of amyloid β-peptide in Alzheimer’s disease has not yet been definitely established, accumulating evidence supports the hypothesis that amyloid β-peptide production and deposition in the brain could be a causative event in Alzheimer’s disease. Dr. Xu explains that the literature indicates amyloid β-peptide itself could be toxic to synapses and the accumulation of amyloid β-peptide could initiate a series of events contributing to cell death, including activation of cell death programs, oxidation of lipids and disruption of cell membranes, an inflammatory response, and possibly neurofibrillary tangle formation, which is a close correlate of neuron loss. Therefore, the problem of production, accumulation, and clearance of amyloid β-peptide in the brain emerges as one of the possible rational approaches for the treatment of Alzheimer’s disease.
Generally, amyloid β-peptides are around 39-43 amino acid long. Studies have shown that the longer amyloid β-peptides are more amyloidogenic and more pathogenic than the shorter ones. Now, Dr. Xu and his colleagues have discovered a new species of amyloid β-peptide that is 46 amino acids long, called Aβ46. This Aβ46 peptide is produced by γ-secretase at a novel cleavage site, the ζ-site. This site also happens to be the site of a mutation found in early-onset familial Alzheimer’s disease called the APP717 or London mutation.
"Another well characterized Alzheimer’s disease-linked amyloid precursor protein mutation, the Swedish mutation, also occurs at a major cleavage site, the β-cleavage site at the N-terminus of amyloid β-peptide," adds Dr. Xu. "Studies have shown that Swedish mutation at the β-cleavage site makes the amyloid precursor protein more susceptible to β-secretase activity. The finding that ζ-cleavage site is the APP717 mutation site suggests that the APP717 mutation may cause enhanced production of the longer amyloid β-peptide, Aβ42, by influencing the ζ-cleavage. Therefore, this finding may open a new avenue for studying the mechanism by which APP717 mutations cause enhanced production of the longer amyloid β-peptide."
Dr. Xu and his colleagues also discovered that γ-secretase cleavage at the new ζ-site is specifically inhibited by compounds known as transition state analogs, but is less affected by compounds known as non-transition state inhibitors. Specifically, some of these inhibitors, which were previously known to inhibit the formation of secreted amyloid β-peptides, were found to cause an intracellular accumulation of an even longer amyloid β-peptide species, Aβ46. "These novel findings provide information important for the strategy of prevention and treatment of Alzheimer’s disease, aimed at the design of γ-secretase inhibitors," concludes Dr. Xu. "Since amyloid β-peptide is produced by the sequential actions of β- and γ-secretases, inhibition of these secretases to reduce the production of amyloid β-peptide is believed to be one of the more promising avenues of treatment of the disease. To date, more than one dozen γ-secretase inhibitors have been developed or identified."
American Society for Biochemistry and Molecular Biology. November 2004.