Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A new species of amyloid peptide

26.11.2004


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

Generally, amyloid â-peptides are around 39-43 amino acid long. Studies have shown that the longer amyloid â-peptides are more amyloidogenic and more pathogenic than the shorter ones. Now, Dr. Xu and his colleagues have discovered a new species of amyloid â-peptide that is 46 amino acids long, called Aâ46. This Aâ46 peptide is produced by ã-secretase at a novel cleavage site, the æ-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 â-cleavage site at the N-terminus of amyloid â-peptide," adds Dr. Xu. "Studies have shown that Swedish mutation at the â-cleavage site makes the amyloid precursor protein more susceptible to â-secretase activity. The finding that æ-cleavage site is the APP717 mutation site suggests that the APP717 mutation may cause enhanced production of the longer amyloid â-peptide, Aâ42, by influencing the æ-cleavage. Therefore, this finding may open a new avenue for studying the mechanism by which APP717 mutations cause enhanced production of the longer amyloid â-peptide."

Dr. Xu and his colleagues also discovered that ã-secretase cleavage at the new æ-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 â-peptides, were found to cause an intracellular accumulation of an even longer amyloid â-peptide species, Aâ46. "These novel findings provide information important for the strategy of prevention and treatment of Alzheimer’s disease, aimed at the design of ã-secretase inhibitors," concludes Dr. Xu. "Since amyloid â-peptide is produced by the sequential actions of â- and ã-secretases, inhibition of these secretases to reduce the production of amyloid â-peptide is believed to be one of the more promising avenues of treatment of the disease. To date, more than one dozen ã-secretase inhibitors have been developed or identified."

Nicole Kresge | EurekAlert!
Further information:
http://www.asbmb.org
http://www.jbc.org

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Supersensitive through quantum entanglement

28.06.2017 | Physics and Astronomy

X-ray photoelectron spectroscopy under real ambient pressure conditions

28.06.2017 | Physics and Astronomy

Mice provide insight into genetics of autism spectrum disorders

28.06.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>