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

More articles from Life Sciences:

nachricht Bolstering fat cells offers potential new leukemia treatment
17.10.2017 | McMaster University

nachricht Ocean atmosphere rife with microbes
17.10.2017 | King Abdullah University of Science & Technology (KAUST)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Ocean atmosphere rife with microbes

17.10.2017 | Life Sciences

Neutrons observe vitamin B6-dependent enzyme activity useful for drug development

17.10.2017 | Life Sciences

NASA finds newly formed tropical storm lan over open waters

17.10.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>