Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers Unveil a New Cause of Familial Alzheimer’s Disease and Find Novel Protective Mechanism

13.02.2014
Researchers in Germany and Japan have found out how a new form of familial (inherited) Alzheimer’s disease (AD) develops and have also detected a new mechanism in nerve cells which reduces the risk for this disease. Altogether, four different forms of inherited Alzheimer’s are now known.

These familial forms are rare, but very aggressive and typically affect individuals before the age of 60. The findings jointly obtained by Dr. Safak Caglayan and Professor Thomas Willnow from the Max Delbrück Center (MDC) Berlin-Buch, Germany, and by Professor Junichi Takagi from the University of Osaka, Japan, have now been published in Science Translational Medicine, 10.1126/scitranslmed.3007747)*.

Currently, about 35 million people suffer from AD worldwide. Those afflicted are confronted with the loss of function and eventual death of their nerve cells, a process which leads to the progressive loss of memory and to dementia. Inheritable (familial) forms of AD are rare. “About 0.5 – 1 per cent,” Professor Willnow estimates. Still, familial forms of the disease are informative for science as they provide insight into the disease’s genetic causes, which probably also play a role in the sporadic form of AD. Sporadic AD is the common form of age-related dementia affecting the vast majority of patients, but its causes are still unclear.

The major culprit in the occurrence of AD is a short protein fragment called amyloid-beta peptide, or A-beta for short. A-beta is produced in the nerve cells from the amyloid precursor protein (APP), a larger protein that is cut into pieces by molecular scissors (secretases). The production of A-beta is a normal physiological process which occurs in the brain of every healthy human being. The reason for the production of A-beta is still a matter of debate, but recent findings suggest that this peptide reduces the activity of nerve cells in order to keep them from overreacting.

A-beta becomes a problem when too much is produced, as is the case in the brain of patients at risk of AD. Overproduction of this peptide impairs the communication between nerve cells, causing memory deficits and cognitive impairment. In addition, too much A-beta results in the deposit of plaques in the brain that damage nerve cells even further. “Since the amount of A-beta in the brain constantly rises with the age of the individual, the risk of developing AD increases dramatically in ageing societies,” Professor Willnow explains.

Nerve cells produce protecting factor
Several years ago, Professor Willnow’s research group discovered that healthy neurons produce a factor which reduces the production of A-beta. This factor is the transport molecule SORLA (sorting protein-related receptor). They showed that mice that do not produce SORLA due to a gene defect accumulate more A-beta than normal mice. The researchers found the same phenomenon in humans: the amount of SORLA produced in the brain of AD patients was often lower than in the brain of individuals not suffering from dementia.

“Genetic studies by many research groups around the world support this hypothesis,” says Professor Willnow. These studies show that specific gene variations of SORLA which cause reduced production of this protecting factor are more often seen in AD patients than in others. This observation suggests that the brain of some individuals produces too little SORLA. “Their risk of developing AD is higher,” Professor Willnow points out. He assumes that high levels of SORLA in the brain slow down the process of AD, whereas low levels of SORLA increase the risk of the disease.

Proven: High levels of SORLA dramatically reduce A-beta
To test their hypothesis, Professor Willnow and his colleagues now wanted to find out if the brain really is protected from A-beta production when levels of SORLA are increased. For this purpose, they generated mice that carry an extra copy of the gene for SORLA in their genome. These transgenic mice not only produced four times as much SORLA in nerve cells as normal mice. Their increased levels of SORLA also drastically reduced the production of A-beta. With this experiment the researchers in Berlin were able to demonstrate that increased production of SORLA indeed protects the brain from too much A-beta.
Protecting factor already active within the nerve cells
In their studies Professor Willnow and his colleagues also uncovered how SORLA works. Normally, A-beta is released from producing cells in order to regulate the communication between the nerve cells. Now the researchers demonstrated that SORLA already gets hold of newly produced A-beta within the nerve cell. SORLA binds A-beta and transports it into a kind of cellular shredder, the lysosomes. “SORLA shuttles some A-beta into the lysomes and reduces the amount of A-beta that is released. Consequently, less A-beta accumulates in the brain and the damage to nerve cells is reduced,” Professor Willnow points out.
Findings also important for familial AD
The importance of these findings in transgenic mice for the human disease was further underscored when Professor Willnow’s group studied one particular mutation in the human SORLA gene found by French researchers in a family suffering from an inheritable form of AD. “We were able to show that the mutation is located exactly where SORLA binds to A-beta. In patients who carry this particular mutation SORLA cannot bind A-beta and shuttle it to lysosomes for destruction. Too much A-beta makes its way out of the nerve cells and increasingly blocks their communication,” Professor Willnow points out.
Screening for small molecules
“Now we are looking for small molecules which are able to increase the production of SORLA in the human brain. In the long run, those substances may be used to protect the brain of patients from overproduction of A-beta and slow down the progression of dementia,” Professor Willnow hopes.

*Lysosomal Sorting of Amyloid-b by the SORLA Receptor Is Impaired by a Familial Alzheimer’s Disease Mutation

Authors: Safak Caglayan1, Shizuka Takagi-Niidome2, Fan Liao3; Anne-Sophie Carlo1, Vanessa Schmidt1, Tilman Burgert1, Yu Kitago2, Ernst-Martin Füchtbauer4, Annette Füchtbauer4, David M. Holtzman3, Junichi Takagi2* and Thomas E. Willnow1*

Affiliations: 1Max Delbrück Center for Molecular Medicine, Berlin, Germany; 2Institute for Protein Research, Osaka University, Osaka, Japan; 3Department of Neurology, Washington University, and Department of Neurology, Hope Center for Neurological Disorders, St. Louis, US; and 4Department of Molecular Biology, Aarhus University, Aarhus, Denmark.

Contact:
Barbara Bachtler
Press Department
Max Delbrück Center for Molecular Medicine (MDC) Berlin-Buch
in the Helmholtz Association
Robert-Rössle-Straße 10
13125 Berlin
Germany
Phone: +49 (0) 30 94 06 - 38 96
Fax: +49 (0) 30 94 06 - 38 33
E-Mail: presse@mdc-berlin.de

Barbara Bachtler | Max-Delbrück-Centrum
Further information:
http://www.mdc-berlin.de/

More articles from Health and Medicine:

nachricht Custom-tailored strategy against glioblastomas
26.09.2016 | Rheinische Friedrich-Wilhelms-Universität Bonn

nachricht New leukemia treatment offers hope
23.09.2016 | King Abdullah University of Science and Technology

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: First-Ever 3D Printed Excavator Project Advances Large-Scale Additive Manufacturing R&D

Heavy construction machinery is the focus of Oak Ridge National Laboratory’s latest advance in additive manufacturing research. With industry partners and university students, ORNL researchers are designing and producing the world’s first 3D printed excavator, a prototype that will leverage large-scale AM technologies and explore the feasibility of printing with metal alloys.

Increasing the size and speed of metal-based 3D printing techniques, using low-cost alloys like steel and aluminum, could create new industrial applications...

Im Focus: New welding process joins dissimilar sheets better

Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of light metals.
Scientists at the University of Stuttgart have now developed two new process variants that will considerably expand the areas of application for friction stir welding.
Technologie-Lizenz-Büro (TLB) GmbH supports the University of Stuttgart in patenting and marketing its innovations.

Friction stir welding is a still-young and thus often unfamiliar pressure welding process for joining flat components and semi-finished components made of...

Im Focus: First quantum photonic circuit with electrically driven light source

Optical quantum computers can revolutionize computer technology. A team of researchers led by scientists from Münster University and KIT now succeeded in putting a quantum optical experimental set-up onto a chip. In doing so, they have met one of the requirements for making it possible to use photonic circuits for optical quantum computers.

Optical quantum computers are what people are pinning their hopes on for tomorrow’s computer technology – whether for tap-proof data encryption, ultrafast...

Im Focus: OLED microdisplays in data glasses for improved human-machine interaction

The Fraunhofer Institute for Organic Electronics, Electron Beam and Plasma Technology FEP has been developing various applications for OLED microdisplays based on organic semiconductors. By integrating the capabilities of an image sensor directly into the microdisplay, eye movements can be recorded by the smart glasses and utilized for guidance and control functions, as one example. The new design will be debuted at Augmented World Expo Europe (AWE) in Berlin at Booth B25, October 18th – 19th.

“Augmented-reality” and “wearables” have become terms we encounter almost daily. Both can make daily life a little simpler and provide valuable assistance for...

Im Focus: Artificial Intelligence Helps in the Discovery of New Materials

With the help of artificial intelligence, chemists from the University of Basel in Switzerland have computed the characteristics of about two million crystals made up of four chemical elements. The researchers were able to identify 90 previously unknown thermodynamically stable crystals that can be regarded as new materials. They report on their findings in the scientific journal Physical Review Letters.

Elpasolite is a glassy, transparent, shiny and soft mineral with a cubic crystal structure. First discovered in El Paso County (Colorado, USA), it can also be...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Paper – Panacea Green Infrastructure?

30.09.2016 | Event News

HLF: From an experiment to an establishment

29.09.2016 | Event News

European Health Forum Gastein 2016 kicks off today

28.09.2016 | Event News

 
Latest News

First-Ever 3D Printed Excavator Project Advances Large-Scale Additive Manufacturing R&D

30.09.2016 | Materials Sciences

New Technique for Finding Weakness in Earth’s Crust

30.09.2016 | Earth Sciences

Cells migrate collectively by intermittent bursts of activity

30.09.2016 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>