Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Mild Injury May Render Brain Cells Vulnerable to Immune Attack

24.10.2002


Drugs to protect the brains of Alzeimer’s patients could result from new finding.



Duke University Medical Center researchers have discovered that a seemingly mild "insult" to the brain could sensitize neurons to attack by immune system proteins that are otherwise protective.

The finding could explain why sufferers of Alzheimer’s and other neurodegenerative diseases significantly worsen following such insults. According to the scientists, such minimal "excitotoxic insults" could include brief seizures, mild head trauma or stroke, or even transient anoxia from fainting while standing too quickly.


The scientists believe that drugs to selectively inhibit the immune proteins could reduce the rate of neural damage in a wide range of neurodegenerative diseases. Such drugs could also protect other organs against damage from autoimmune diseases such as lupus and rheumatoid arthritis, in which the immune system attacks body tissues, said the scientists.

In an article in the October 24, 2002, Neuron, Zhi-Qi Xiong and James McNamara report studies of brain cell cultures that reveal how the set of immune proteins, called "complement," can kill neurons. The research was supported by the National Institutes of Health.

Complement proteins circulate in the blood in an inactive form, but when triggered by infection or other invaders, they form complexes that can attack the invaders.

"For a decade or more, there have been studies in which complement proteins were detected in the vicinity of senile plaques of patients with Alzheimer’s disease and also in the brain of other neurodegenerative diseases," said McNamara, who is professor and chair of the medical center’s department of neurobiology . According to McNamara, while this association suggested that complement could harm neurons, evidence also existed that complement could promote removal of a damaging protein that causes the plaques in Alzheimer’s disease.

The reality, Xiong and McNamara discovered, seems more complicated. The complement immune system pathway consists of an "early activation" pathway that can be protective in Alzheimer’s disease, and a "terminal" pathway, in which the proteins combine to create a "membrane attack complex." It is the terminal pathway and this complex that damages neurons sensitized to complement attack by mild brain insult, said McNamara.

"Basically, we have discovered how an insult like transient ischemic attacks, minimal drop in blood pressure or a minimal blow to the head could facilitate the transition from the early activation pathway to the terminal membrane attack pathway, and transform a protective effect into a damaging effect on the brain," said McNamara.

Initial clues that complement could attack brain cells came from the Duke scientists’ earlier studies of a rare childhood brain disease called Rasmussen’s encephalitis.

"We observed that in this autoimmune disease, even though the immune system is constantly attacking the brain, the progressive loss of neurological function in these children occurred in a stepwise fashion, following flurries of seizures," said McNamara. The scientists found that the brains of children suffering from the disease showed evidence of activation of complement, and the complement proteins were concentrated in the neurons. Also, said McNamara, the scientists’ studies of an animal model of the disease showed similar attack by complement.

What’s more, he said, studies by other researchers had demonstrated in animal models and cell cultures that fleeting insults can damage neurons by causing an "excitotoxic" overload of the neurotransmitter glutamate.

Earlier brain tissue culture studies had shown that complement could damage brain cells called astrocytes preferentially over neurons, said McNamara.

"This didn’t make sense," said McNamara. "In our tissue culture studies, the astrocytes were preferentially damaged, but in brains, the complement was deposited on neurons. And so we reasoned that perhaps there was an interaction between the excessive excitation mediated by glutamate and a neuron’s sensitivity to attack by complement."

In their experiments reported in Neuron, Xiong and McNamara exposed cultures of neurons and astrocytes, first to modest levels of glutamate, as might be generated by a mild insult to the brain. When they next exposed these same cultures to activated complement proteins, the neurons were preferentially killed.

Their studies also showed that the damage was specifically caused by the membrane attack pathway of complement and not by the early activation pathway. And, they found that the glutamate treatment sensitized neurons, but not astrocytes, to attack by complement.

Finally, the scientists found that the excitotoxic sensitization of neurons required both calcium and chemicals called "reactive oxygen species." While the scientists do not understand these requirements, said McNamara, they believe that the finding might offer further clues to the metabolic pathway by which the neuron’s defenses against complement are compromised. Importantly, said McNamara, their finding raises the possibility of protecting the brains of patients with neurodegenerative disease.

"The identification of a small-molecule inhibitor of the terminal pathway of complement may prove to be tremendously beneficial to patients with late-stage neurodegenerative disease, reducing the rate of brain injury," he said.

What’s more, said McNamara, such drugs "could be helpful in diseases of many other organs, not just the brain, in which inappropriate activation of complement damages the tissues, like rheumatoid arthritis, lupus and others." McNamara emphasized the importance of basic studies of rare diseases to such discoveries.

"I think this is one of countless examples in human biology in which study of a rare disease, in this case Rasmussen’s encephalitis, sheds light on mechanisms of common diseases," he said. "We would have been unlikely to have gained this invaluable insight into the immune system and the brain, had we not been studying Rasmussen’s encephalitis."


For additional information, contact:
Dennis Meredith | phone: (919) 681-8054 | email: dennis.meredith@duke.edu

Dennis Meredith | EurekAlert!
Further information:
http://www.duke.edu/

More articles from Health and Medicine:

nachricht Correct connections are crucial
26.06.2017 | Charité - Universitätsmedizin Berlin

nachricht One gene closer to regenerative therapy for muscular disorders
01.06.2017 | Cincinnati Children's Hospital Medical Center

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: 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

Study shines light on brain cells that coordinate movement

26.06.2017 | Life Sciences

Smooth propagation of spin waves using gold

26.06.2017 | Physics and Astronomy

Switchable DNA mini-machines store information

26.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>