A new species of amyloid peptide

Scientists have identified a new, longer species of amyloid в-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 в-peptides in the brain. These amyloid
в-peptides are derived from a large amyloid precursor protein through a series of cleavage events. Under normal conditions,
cleavage first by б-secretase and then by г-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 в-secretase and г-secretase to produce a soluble ectodomain along with the full-length amyloidogenic amyloid
в-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 в-peptide in Alzheimer's disease has not yet been definitely established,
accumulating evidence supports the hypothesis that amyloid в-peptide production and deposition in the brain could be a
causative event in Alzheimer's disease. Dr. Xu explains that the literature indicates amyloid в-peptide itself could be toxic
to synapses and the accumulation of amyloid в-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 в-peptide in the brain emerges as one of the possible rational approaches for the
treatment of Alzheimer's disease.


Generally, amyloid в-peptides are around 39-43 amino acid long. Studies have shown that the longer amyloid в-peptides are
more amyloidogenic and more pathogenic than the shorter ones. Now, Dr. Xu and his colleagues have discovered a new species of
amyloid в-peptide that is 46 amino acids long, called Aв46. This Aв46 peptide is produced by г-secretase at a novel cleavage
site, the ж-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 в-cleavage site at the N-terminus of amyloid в-peptide," adds Dr. Xu. "Studies have shown that
Swedish mutation at the в-cleavage site makes the amyloid precursor protein more susceptible to в-secretase activity. The
finding that ж-cleavage site is the APP717 mutation site suggests that the APP717 mutation may cause enhanced production of
the longer amyloid в-peptide, Aв42, by influencing the ж-cleavage. Therefore, this finding may open a new avenue for studying
the mechanism by which APP717 mutations cause enhanced production of the longer amyloid в-peptide."


Dr. Xu and his colleagues also discovered that г-secretase cleavage at the new ж-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 в-peptides, were found to
cause an intracellular accumulation of an even longer amyloid в-peptide species, Aв46. "These novel findings provide
information important for the strategy of prevention and treatment of Alzheimer's disease, aimed at the design of г-secretase
inhibitors," concludes Dr. Xu. "Since amyloid в-peptide is produced by the sequential actions of в- and г-secretases,
inhibition of these secretases to reduce the production of amyloid в-peptide is believed to be one of the more promising
avenues of treatment of the disease. To date, more than one dozen г-secretase inhibitors have been developed or identified."



The Journal of Biological Chemistry's Papers of the Week is an online feature which highlights the top one percent of papers
received by the journal. Brief summaries of the papers and explanations of why they were selected for this honor can be
accessed directly from the home page of the Journal of Biological Chemistry online at jbc.


The American Society for Biochemistry and Molecular Biology (ASBMB) is a nonprofit scientific and educational organization
with over 11,000 members in the United States and internationally. Most members teach and conduct research at colleges and
universities. Others conduct research in various government laboratories, nonprofit research institutions, and industry.



Founded in 1906, the Society is based in Bethesda, Maryland, on the campus of the Federation of American Societies for
Experimental Biology. The Society's primary purpose is to advance the sciences of biochemistry and molecular biology through
its publications, the Journal of Biological Chemistry, The Journal of Lipid Research, Molecular and Cellular Proteomics, and
Biochemistry and Molecular Biology Education, and the holding of scientific meetings.


For more information about ASBMB, see the Society's website at asbmb.


Contact: Nicole Kresge

nkresgeasbmb

301-634-7415

American Society for Biochemistry and Molecular Biology