CJD protein sheds light on Alzheimer's

A “surprise discovery” has allowed scientists to block Alzheimer's disease, The Independent reported. The newspaper said that researchers developing drugs to treat the brain disorder Creutzfeldt-Jakob Disease (CJD) “have unexpectedly blocked the onset of Alzheimer's disease, the most common cause of dementia”.

However, it is not correct to say that researchers have been able to “block” the onset of Alzheimer’s disease. The study in question carried out laboratory and animal experiments to investigate the binding between two types of protein. One of the proteins investigated (called the amyloid beta protein) builds up in Alzheimer’s disease. An abnormal form of the other protein (called the prion protein) causes CJD. Scientists found that blocking the binding of the proteins stopped the amyloid protein from affecting nerve signals in mouse brain samples and in the brains of live rats.

Alzheimer’s is a complex disease and is caused by the death of nerve cells in certain areas of the brain. What triggers the death of nerve cells in this disease is still not fully understood, and blocking the effects of the amyloid protein in this way may not be sufficient to stop nerve cells dying.

The interesting finding of this study suggests it could be worth testing antibodies that target prion proteins in Alzheimer’s disease. These antibodies have reportedly already been prepared for testing in human diseases such as CJD, which may mean they could be tested on Alzheimer’s disease in humans sooner. However, it is likely that more testing of their effects in animals will be needed before human testing is attempted.

Where did the story come from?

The study was carried out by researchers from University College Dublin and other research centres in Ireland and the UK. It was funded by the Science Foundation Ireland, the Health Research Board, a University College Dublin seed funding grant, the UK Medical Research Council and the Department of Health.

The study was published in the peer-reviewed scientific journal Nature Communications.

The Independent, The Daily Telegraph and Daily Mirror covered this study. The Independent and Telegraph reported that this research was in rodents, but the Mirror did not. The Independent ’s suggestion that scientists have “blocked the onset of Alzheimer's disease” is not correct. They have only shown that a single effect of the amyloid beta protein on nerve cells (neurones) has been prevented, which is not the same as blocking the development of Alzheimer’s disease.

What kind of research was this?

This animal research looked at the interaction between certain proteins involved in the brain conditions Creutzfeldt-Jakob Disease (CJD) and Alzheimer’s disease. These proteins are respectively known as the prion protein and amyloid beta. Both these proteins are present in normal brain tissue, but they are also involved in disease. An abnormal form of prion protein is the cause of CJD, a degenerative brain disorder. In people with Alzheimer’s disease, amyloid beta builds up in the brain and forms abnormal deposits, known as plaques. Amyloid beta is thought to affect the function of nerve cells directly, by influencing the strength of connections between the nerve cells (synapses) and, therefore, affecting memory. The build-up of amyloid beta is also thought to contribute to the death of neurones in the brain, which is the cause of the symptoms of the disease.

Previous research has suggested that amyloid beta might need to bind to the prion protein to have an adverse effect on nerve cell function. The researchers discuss previous research that looked at blocking this binding using antibodies, types of special proteins that the immune system uses to help defend the body. Antibodies have the ability to bind to foreign substances, such as molecules on the surface of bacteria and viruses, allowing the immune system to identify and attack them. The researchers say that in a previous study, an antibody against prion protein was able to prevent it from binding to amyloid beta, reducing its toxic effects on neurones in the laboratory and in a mouse model of Alzheimer’s disease. However, other studies have suggested that not all the adverse effects of amyloid beta seem to need the prion protein to be present.

In this study, the researchers wanted to repeat some of these previous experiments to confirm their findings and to look further at the effects on neurone function of blocking the interaction between amyloid beta and prion protein.

This type of early study helps researchers understand what might be going on in a disease, and suggests potential “targets” for new drugs or treatments. These treatments can then be tested in the laboratory and on animals to try and identify which ones have the most promise for testing in humans. While experimental models in the laboratory and animal models of the disease are useful research tools, they are not exactly the same as human disease, and treatments do not always have the same effect when they are tested in humans.

What did the research involve?

The researchers carried out a wide range of experiments. First, they generated a standardised form of amyloid beta that they could use in their experiments, called amyloid beta-derived diffusible ligand (ADDL). They noted that this preparation is not identical to the brain-derived amyloid beta.

Next, they carried out some tests in brain slices from mice, which were taken from a region of the brain called the hippocampus. This is the area affected in Alzheimer’s disease. They tested the effects of ADDL on neurones in these brain slices. They specifically looked at the effect on a nerve signalling phenomenon known as “long-term potentiation”, which strengthens the connection between neurones and is involved in learning and memory. They then tested whether prion protein needed to be present for ADDL to have an effect within the brain. To do this, they repeated their experiments using brain slices from mice that were genetically engineered to lack the prion protein. As well as using their laboratory-generated ADDL, they also repeated these experiments using amyloid beta extracted from the brain of a person with Alzheimer’s disease.

They then further investigated how the prion protein and amyloid beta interact. They did this to identify key parts of the proteins that allow interaction to occur, so they could target these with antibodies to see if this would stop the interaction. They then tested a range of antibodies against different parts of the prion protein to see whether this would stop it binding to amyloid beta.

Once they identified antibodies that blocked this binding, they looked at whether they could stop the effects of amyloid beta on long-term potentiation in mouse brain slices. Finally, they tested the effects of one of these antibodies in living rats. Again, they looked at the effects on long-term potentiation, which normally occurs in response to stimulating the rat’s brain with high-frequency electrical stimulation. They injected the rats’ brains with amyloid beta extracted from a human brain with Alzheimer’s and looked at the effect on long-term potentiation. They then tested whether pre-injecting the brains with the antibody before injecting amyloid beta blocked it from having an effect.

What were the basic results?

The researchers found that both amyloid beta preparations (one made in the lab and the other extracted post mortem from the brain of a person with Alzheimer’s disease) inhibited long-term potentiation in the brain slices from normal mice, but not from genetically engineered mice lacking prion protein. This showed that the prion protein needed to be present for amyloid beta to have this effect.

The researchers found that two anti-prion antibodies, called ICSM-18 and ICSM-35, that have been tested in human prion disease could block the binding of amyloid beta and prion protein in the laboratory. These antibodies were also able to stop amyloid beta from having an effect on long-term potentiation in mouse brain slices. ICSM-18 was also shown to stop the effect of amyloid beta on long-term potentiation in live rats.

How did the researchers interpret the results?

The researchers concluded that their findings confirm that prion protein binds to amyloid protein and facilitates amyloid’s damaging effects on the function of nerve cells.

They say that the two main antibodies they tested, ICSM-18 and ICSM-35, could block the effects of amyloid beta on neurone signalling (long-term potentiation). This confirms that these antibodies are candidates for testing as potential treatments for Alzheimer’s disease, either on their own or in combination.

Conclusion

This animal research supports the theory that the prion protein plays a role in the effects that the amyloid beta protein has on neurones. It also suggests that using antibodies can prevent at least one effect of amyloid protein on the nerve cells.

It is important to note that the study looked at only one effect of amyloid beta on nerve cells: the effect on one aspect of neurone signalling called long-term potentiation, which is involved in learning and memory. Alzheimer’s is a complex disease and is largely caused by the death of neurones in certain areas of the brain. What causes the death of neurones in this disease is still not fully understood. Blocking the effects of amyloid beta on long-term potentiation may not be sufficient to stop neurones dying and, therefore, to affect disease progression.

The interesting finding of this study suggests that antibodies that target the prion protein could be tested for their effects in Alzheimer’s disease. These antibodies have reportedly already been extensively tested in mice and prepared for use in human testing for prion diseases, such as CJD. This means that they may be able to be tested in human Alzheimer’s disease sooner than if these steps had not been taken. However, it is likely that more testing in animals will be needed before human testing is attempted.