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.
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
Dr. Marcus Neitzert | idw
Electrical 'switch' in brain's capillary network monitors activity and controls blood flow
27.03.2017 | Larner College of Medicine at the University of Vermont
Laser activated gold pyramids could deliver drugs, DNA into cells without harm
24.03.2017 | Harvard John A. Paulson School of Engineering and Applied Sciences
Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.
The results will be published on March 22 in the journal „Astronomy & Astrophysics“.
Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...
Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.
Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...
In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.
Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.
Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...
20.03.2017 | Event News
14.03.2017 | Event News
07.03.2017 | Event News
27.03.2017 | Earth Sciences
27.03.2017 | Life Sciences
27.03.2017 | Life Sciences