Arthritis may block Alzheimer's

Behind the Headlines

Monday August 23 2010

Having rheumatoid arthritis may protect against Alzheimer's

A protein produced in arthritis may “protect against the development of Alzheimer's disease,” reported BBC News. US research on mice has discovered that a protein called GM-CSF, produced in rheumatoid arthritis, may trigger the immune system to destroy the protein plaques found in Alzheimer’s disease.

This research used mice that had been genetically engineered to have a condition similar to Alzheimer’s. It found that these mice performed better in tests of memory and learning after they had been given a GM-CSF injection for 20 days. The protein also helped normal mice to improve their performance in the tests. After the injections, the mouse brains also contained increased levels of microglial cells, types of cells that engulf debris and foreign organisms. It is possible that these  microglial cells could combat the build-up of amyloid proteins that characterise Alzheimer’s disease.

The findings help to further the understanding of how rheumatoid disease may offer some protection against the development of Alzheimer’s. However, it remains to be seen whether this research could be a first step towards investigating GM-CSF as a potential treatment, which will now need further testing.

 

Where did the story come from?

The study was carried out by researchers from the University of South Florida’s Byrd Alzheimer’s Centre and Research Institute, and Saitama Medical University, Japan. Funding was provided by the Byrd Alzheimer’s Centre and Research Institute, the Eric Pfeiffer Chair for research on Alzheimer’s disease, the Florida Alzheimer’s Disease Research Centre, and the James H. and Martha M. Porter Alzheimer’s Fund. The study was published in the peer-reviewed Journal of Alzheimer’s Disease.

The Daily Mail, Daily Express and BBC News have accurately reflected the findings of this animal research, and make it clear that this was early research conducted in mice.

 

What kind of research was this?

This was research in mice, which aimed to further the understanding of why people with rheumatoid arthritis (RA) appear to have a reduced risk of Alzheimer’s disease (AD). It has often been assumed that this reduced risk was due to the use of anti-inflammatory drugs to treat RA, but this study investigated whether certain immune system proteins that have increased activity in RA could have an influence on Alzheimer’s risk. The proteins of interest were macrophage (M-CSF), granulocyte (G-CSF) and granulocyte-macrophage colony-stimulating factors (GM-CSF). 

Animal studies can provide valuable information on disease processes and the factors that may be involved in the development of a disease. However, mice are different from humans and the findings in this exploratory mouse model of AD may not be directly transferable to the disease in humans.

 

What did the research involve?

This research involved mice that were genetically engineered to accumulate a protein called beta amyloid in their brains. Accumulation of  “plaques” containing this fibrous protein are one of the characteristic findings in the brains of people with AD; hence these mice are an animal model of AD.

An area of the brain called the hippocampus, which is involved in long-term memory and awareness of time and place, is often affected in AD. The researchers injected either the M-CSF, G-CSF or GM-CSF protein into the hippocampus on one side of the mouse brain and a control solution in the other half of the hippocampus. One week later they examined the hippocampus to compare the effects of the colony-stimulating factor proteins and the control solution, measuring the amount of amyloid protein in each half of the hippocampus. In the mice genetically engineered to have AD, the GM-CSF protein in particular reduced the amount of amyloid in the hippocampus. M-CSF and G-CSF reduced amyloid to a lesser extent.

On the basis of this finding, the researchers carried out further experiments using GM-CSF. Groups of both normal mice and the genetically engineered AD-model mice had their cognitive function examined with various tests. One involved a water maze partitioned off into different sections, where the mice had to swim to find the correct exit. The test was repeated on numerous occasions and the exit position also varied. The number of errors the mice made in finding the exit was assessed.

They then injected GM-CSF under the mice’s skin on 20 consecutive days before repeating the tests and assessing the amount of amyloid in the hippocampus. They again compared these GM-CSF  injections with control solution in normal and genetically engineered AD-model mice.

 

What were the basic results?

The researchers found that GM-CSF injections reversed cognitive impairment in the AD-model mice, and that they performed equally well or better than the normal mice on the cognitive tests. Normal mice injected with GM-CSF also performed equally well or better than normal mice who had not been injected.

In the AD mice there was a 50%–60% reduction in the amount of amyloid in the brain after the GM-CSF injections. They also found an increase in microglial cells in the brain, which are part of the immune system and have a similar role to the white blood cells that phagocytose (eat up) debris and foreign organisms. It is believed that the microglia may have some role in destroying the accumulated amyloid.

 

How did the researchers interpret the results?

The researchers conclude that their findings suggest that Leukine (a synthetic form of human GM-CSF that is already used as a treatment for some other conditions) should be tested as a treatment for AD.

 

Conclusion

This valuable scientific research has furthered the understanding of how the GM-CSF protein, which is increased in rheumatoid arthritis, could give some protection against Alzheimer’s disease. As the researchers suggest, it is possible that GM-CSF acts by “recruiting” microglia to the brain, which then attack the characteristic amyloid plaques of Alzheimer's.

This type of animal model is currently the best way of studying potential Alzheimer’s drug treatments in the laboratory. However, it should be remembered that Alzheimer’s is a complex disease and animal models may not be fully representative of the brain changes and cognitive problems seen in the human form of the disease. Also, the cognitive tests that can be performed in these mice may not capture the full range of memory impairment and characteristic cognitive changes that occur in humans with AD, i.e. problems with understanding, planning and carrying out normal daily tasks, difficulty in recognising objects and people, and language impairment. These differences may mean that success in treating these animal models may not be translated into success in humans.

As lead researcher Dr Huntingdon Potter reportedly told BBC News, these findings “provide a compelling explanation for why rheumatoid arthritis is a negative risk factor for Alzheimer's disease.” The findings may help further the understanding of how rheumatoid disease may offer some protection against the development of AD, but whether this animal research could be a first step towards investigating this protein as a potential treatment for AD remains to be seen.

Leukine, a synthetic form of human GM-CSF, has already been tested in humans for other conditions and is usually used to increase white cell count in people receiving chemotherapy to treat blood cancers. Given that Leukine is currently clinically used in some countries, it may be easier to reach the stage of testing the drug in humans with AD. However, there would still need to be safety and efficacy testing to see whether Leukine would be suitable for the treatment of AD in humans. Leukine itself is not currently licensed for use in the UK, and in the US some formulations have been withdrawn due to reports of side-effects. Synthetic forms of G-CSF, another of the proteins tested,  have been granted a clinical license in the UK. However, these are generally only used by experienced specialists providing care to severely ill people.

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Arthritis 'cuts Alzheimer's risk'. BBC News, August 23 2010

Arthritis may hold the key to beating Alzheimer's as protein released reverses memory loss. Daily Mail, August 23 2010

Cancer drug could help cure dementia. Daily Express, August 23 2010

Links to the science

Boyd TD, Bennett SP, Mori T et al. GM-CSF Upregulated in Rheumatoid Arthritis Reverses Cognitive Impairment and Amyloidosis in Alzheimer Mice. Journal of Alzheimer's Disease, puiblished online June 16 2010

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