Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers find another piece in Alzheimer’s puzzle

12.11.2013
The protein spastin cuts off supply lines inside nerve cells

A team of German and American researchers has added another piece to the puzzle of what causes Alzheimer disease. They have found that a protein called “spastin” plays a previously unsuspected role: spastin is able to cut off the supply lines inside nerve cells, causing their death.

Therefore, substances which specifically inhibit this protein could have a positive effect on the progress of the disease.

Scientists at the Bonn site of the German Center for Neurodegenerative Diseases (DZNE), the caesar research center and the Hamburg Outstation of the Max Planck Institute for Neurological Research took the lead in these investigations. The study was published in the EMBO Journal.

Alzheimer disease causes the memory to fade, ending with complete disorientation and dementia. It also triggers the death of vast quantities of nerve cells in the brain. At present, the causes of Alzheimer’s are only partly understood. The disease is said to be “multifactorial”. Researchers in Bonn, Hamburg and the US have now identified another protagonist called “spastin”. This protein is not new to the field of neurodegenerative diseases. Pathological changes to this protein are considered to be the main cause of hereditary spastic paraplegia. “Mutated spastin damages the cells in the spinal medulla, causing paralysis of the legs. We have now found that spastin, in this case its healthy form, can damage brain cells if not controlled properly. This was a surprise, because Alzheimer research has paid only scant attention to spastin so far,” says neuroscientist Eva-Maria Mandelkow. She is a researcher on Alzheimer disease and cooperates closely with her husband Eckhard Mandelkow. The couple runs labs both in Bonn and Hamburg.

During experiments with cell cultures, the Mandelkow team – including first author Hans Zempel, who is a PhD student at the DZNE in Bonn – found that spastin can damage the supply lines inside the dendrites. Dendrites are fine ramifications of the cell body by which the nerve cell receives stimuli from other cells. But cellular contacts wither if substances important for the cell’s metabolism are not transported properly. If the supply lines – known as microtubules – are severed, the dendrites and ultimately also the nerve cells will perish. The researchers also observed this reaction in their laboratory experiments.

A fatal chain reaction

It is known that the number of microtubules in the nerve cells diminish in cases of Alzheimer disease. This affects not only the delicate dendrites but also the axon, a long cell extension by which the nerve cell transmits signals. “The factors which cause the decline of the microtubules do not necessarily appear to be the same for dendrites and axons,” remarks Eva-Maria Mandelkow. “Our investigations are now creating a clearer picture of why the microtubules in the dendrites disappear. We have been able to prove that the effect of spastin is part of a chain reaction which involves the proteins A-Beta and Tau, among others.”

A-Beta and Tau have long been held responsible for brain pathology in Alzheimer disease. These proteins are normally isolated, but in cases of Alzheimer they become sticky and form protein clumps that appear as the typical “plaques” and “tangles” in Alzheimer brains.

The scientists treated nerve cells with aggregates of the protein A-Beta, thus triggering a sequence of events. Most specifically, the cells now lost control over the proper distribution of Tau proteins, which accumulated in the dendrites. This brought about a chemical change in the microtubules there. “The microtubules became more susceptible to spastin. The protein has the effect of molecular scissors which cut the microtubules into pieces,” says the neuroscientist.

In the healthy organism, this function is strictly regulated. In itself, it is nothing special, because microtubules are constantly broken down and replaced by new ones. However, in Alzheimer disease, this breakdown process gets out of control. “The natural effect of spastin is enhanced. As a result, the microtubules are chopped to pieces,” says Eva-Maria Mandelkow.

Therapeutic potential

In a commentary in the EMBO Journal, US researchers Daphney Jean and Peter Baas, who were not involved in the current study, speculate that some of the experimental substances against Alzheimer could reinforce the negative effect of spastin. They note that at present, substances are being tested which improve the cohesion of the microtubules, but this may not hinder the scissor effect of spastin. Rather the opposite. This is due to the structure of the elongated microtubules, which are naturally made up of stable and comparatively unstable segments. Stabilizing substances cause the unstable segments to shrink while the stable segments grow. Such microtubules provide a greater contact area for spastin. This is because the protein prefers to cut through the stable segments of the microtubules.

A suitable therapeutic approach could be to specifically inhibit the effect of spastin. “Our results indicate that substances which block spastin may have a positive effect on the progress of Alzheimer. However, we have to be careful with prognoses,” says Eva-Maria Mandelkow. “Alzheimer is a disease with many facets and picking just one is unlikely to be enough. However, the important point is that we have identified a puzzle piece which will help us understand the disease better.”

Original publication
“Amyloid-ß oligomers induce synaptic damage via Tau-dependent microtubule severing by TTLL6 and spastin”, Hans Zempel, Julia Luedtke, Yatender Kumar, Jacek Biernat, Hana Dawson, Eckhard Mandelkow, Eva-Maria Mandelkow, The EMBO Journal, online publication dated September 24, 2013, http://dx.doi.org/10.1038/emboj.2013.207
Commentary (“Have you seen?”)
“It cuts two ways: microtubule loss during Alzheimer disease”, Daphney C. Jean, Peter W. Baas, The EMBO Journal, online publication dated September 27, 2013, http://dx.doi.org/doi:10.1038/emboj.2013.219

Dr. Marcus Neitzert | idw
Further information:
http://www.dzne.de

More articles from Health and Medicine:

nachricht Why might reading make myopic?
18.07.2018 | Universitätsklinikum Tübingen

nachricht Unique brain 'fingerprint' can predict drug effectiveness
11.07.2018 | McGill University

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 evidence on the source of extragalactic particles

For the first time ever, scientists have determined the cosmic origin of highest-energy neutrinos. A research group led by IceCube scientist Elisa Resconi, spokesperson of the Collaborative Research Center SFB1258 at the Technical University of Munich (TUM), provides an important piece of evidence that the particles detected by the IceCube neutrino telescope at the South Pole originate from a galaxy four billion light-years away from Earth.

To rule out other origins with certainty, the team led by neutrino physicist Elisa Resconi from the Technical University of Munich and multi-wavelength...

Im Focus: Magnetic vortices: Two independent magnetic skyrmion phases discovered in a single material

For the first time a team of researchers have discovered two different phases of magnetic skyrmions in a single material. Physicists of the Technical Universities of Munich and Dresden and the University of Cologne can now better study and understand the properties of these magnetic structures, which are important for both basic research and applications.

Whirlpools are an everyday experience in a bath tub: When the water is drained a circular vortex is formed. Typically, such whirls are rather stable. Similar...

Im Focus: Breaking the bond: To take part or not?

Physicists working with Roland Wester at the University of Innsbruck have investigated if and how chemical reactions can be influenced by targeted vibrational excitation of the reactants. They were able to demonstrate that excitation with a laser beam does not affect the efficiency of a chemical exchange reaction and that the excited molecular group acts only as a spectator in the reaction.

A frequently used reaction in organic chemistry is nucleophilic substitution. It plays, for example, an important role in in the synthesis of new chemical...

Im Focus: New 2D Spectroscopy Methods

Optical spectroscopy allows investigating the energy structure and dynamic properties of complex quantum systems. Researchers from the University of Würzburg present two new approaches of coherent two-dimensional spectroscopy.

"Put an excitation into the system and observe how it evolves." According to physicist Professor Tobias Brixner, this is the credo of optical spectroscopy....

Im Focus: Chemical reactions in the light of ultrashort X-ray pulses from free-electron lasers

Ultra-short, high-intensity X-ray flashes open the door to the foundations of chemical reactions. Free-electron lasers generate these kinds of pulses, but there is a catch: the pulses vary in duration and energy. An international research team has now presented a solution: Using a ring of 16 detectors and a circularly polarized laser beam, they can determine both factors with attosecond accuracy.

Free-electron lasers (FELs) generate extremely short and intense X-ray flashes. Researchers can use these flashes to resolve structures with diameters on the...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Leading experts in Diabetes, Metabolism and Biomedical Engineering discuss Precision Medicine

13.07.2018 | Event News

Conference on Laser Polishing – LaP: Fine Tuning for Surfaces

12.07.2018 | Event News

11th European Wood-based Panel Symposium 2018: Meeting point for the wood-based materials industry

03.07.2018 | Event News

 
Latest News

Machine-learning predicted a superhard and high-energy-density tungsten nitride

18.07.2018 | Materials Sciences

NYSCF researchers develop novel bioengineering technique for personalized bone grafts

18.07.2018 | Life Sciences

Why might reading make myopic?

18.07.2018 | Health and Medicine

VideoLinks
Science & Research
Overview of more VideoLinks >>>