Targeting inflammation 'could help treat Alzheimer's disease'

“Blocking brain inflammation ‘halts Alzheimer’s disease’,” BBC News reports. Mice with symptoms similar to Alzheimer’s disease were given a drug that blocked the production of immune cells, which cause inflammation. They showed an improvement in symptoms compared with mice who had not been given the drug. 

Inflammation – where immune cells cause swelling of surrounding tissue – has long been associated with Alzheimer’s. However, it is unclear whether inflammation causes Alzheimer’s or is a by-product of an underlying factor.

This research tentatively suggests inflammation is involved in the progression of the disease, and it can be reduced by targeting it.

Researchers first found that in the human form of Alzheimer’s disease, the brain’s immune cells (microglial cells) multiplied more rapidly in and around the protein clumps called amyloid-ß plaques. 

They then worked out a way of blocking this multiplication process in mice bred to have an Alzheimer’s-like disease. This improved the mice’s performance in memory and behavioural tasks, although the amount of amyloid-ß plaques did not change.

The treatment used on the mice has not yet been tested in humans, and there are no guarantees it will be safe or work as well.

As this is very early-stage research, we should be cautious in interpreting too much. However, it does add evidence to the idea that a person’s immune system plays a role in the disease, and could allow researchers to develop drugs that target the immune system.

This is a relatively new focus compared with previous efforts, which focused on trying to prevent or remove the amyloid-ß plaques and proved largely unsuccessful.  

Where did the story come from?

The study was carried out by researchers from the University of Southampton and Lancaster University, and was funded by the Medical Research Council and Alzheimer’s Research UK.

It was published in the peer-reviewed science journal Brain on an open access basis, meaning you can read it for free online.

The UK’s media coverage was generally accurate. BBC News gave optimistic but balanced coverage, quoting experts who said the research was “an exciting discovery” and “encouraging”.

They did, however, add a note of caution from Dr Mark Dallas, lecturer in Cellular and Molecular Neuroscience at the University of Reading, who said: “While this basic science research provides strong evidence, the challenge will now be to develop medicines for people with dementia, so we await the development of clinical treatments with interest. Too often, this has been the stumbling block in turning observations in the laboratory into a workable therapy.” 

What kind of research was this?

This study used humans and mice to investigate the role of the immune system in Alzheimer’s disease.

A range of new and old evidence suggests the activity and multiplication of microglial cells – the brain’s main immune cells – might be an important driver in the progression of Alzheimer’s disease.

This study wanted to see what the microglial cells were doing in both humans and mice, and see if researchers could prevent some of the damage the cells might be orchestrating in mice using a targeted drug. 

What did the research involve?

Mice bred to have an Alzheimer’s-like disease were fed a diet laced with a chemical called GW2580 for three months before carrying out a set of behaviour tasks. Their task performance was compared with a similar group of mice with an Alzheimer’s-like disease who hadn’t been given the drug.

The GW2580 molecule blocks a receptor protein called a colony stimulating factor 1 receptor (CSF1R), which, when activated, spurs the microglial cells into multiplying and facilitating an immune response in the brain. In short, the GW2580 was a targeted way of trying to block the activity of the microglial-mediated immune response.

The human experiments analysed genetic material in the brain cells of people who died with Alzheimer’s disease. Brain cells from 10 people with Alzheimer’s were compared with nine without. These were also compared with brain cells from mice to see if similar Alzheimer’s-related processes were occurring across species.

The main analysis compared the behavioural task performance of mice given the microglial cell-blocking agent GW2580 with mice who had not to see if the drug was improving the disease.

The researchers also compared mice and human brain cells for similarities and differences in how immune signals and cells were interacting and functioning to tease out the underlying mechanism behind the disease. 

What were the basic results?

The key results were:

• In human brain cells, microglial multiplication was higher in those with Alzheimer’s disease than those without, and correlated with disease severity and progression.
• Feeding mice GW2580 did successfully block some of the microglial activation and multiplication.
• Feeding mice GW2580 prevented many of the behavioural problems seen in the mice not given the drug, and caused “significant recovery of the deficits in short-term memory”. It also prevented some of the degradation in the nerve connections in the brain found in the untreated Alzheimer’s-like disease. 
• The number of amyloid-ß plaques remained unchanged.   

How did the researchers interpret the results?

The researchers concluded that, “Our results provide the first proof of the efficacy of CSF1R inhibition [by GW2580] in models of Alzheimer’s disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer’s disease.” 

Conclusion

This study provided proof of concept that – in mice – you can use an oral drug to successfully prevent behavioural, memory and brain cell problems associated with the progression of an Alzheimer’s-like disease.

This study involved blocking the activity of microglial cell activation and multiplication – a process thought to affect the progression of the disease.

These findings provide an exciting foundation for further work to explore whether a similar effect is possible in humans.

As the main part of the study involved mice, we can’t be sure that a similar effect is possible in humans. Only direct experimentation in humans will demonstrate that.

A potential downside of targeting the immune system is it provides a crucial role in fighting off all sorts of diseases. If you block the immune system, there are probably going to be important side effects or risks involved.

As this is early-stage research, we shouldn’t speculate too widely on potential future drug development, as there are no guarantees this will be successful.

The results are a step forward in understanding the role of the immune system in Alzheimer’s disease development and progression, and are part of wider efforts to find a prevention or cure. 

Links To The Headlines

Blocking brain inflammation ‘halts Alzheimer’s disease’. BBC News, January 8 2016

Alzheimer’s treatment closer as brain inflammation shown to be key. The Guardian, January 8 2016

Alzheimer’s: Curbing inflammation in the brain could help combat effects of disease, study finds. The Independent, January 8 2016

Doctors close to ‘curing’ Alzheimer’s and hope for new drugs breakthrough. The Sun, January 8 2016

Links To Science

Olmos-Alonso A, Schetters STT, Sri S, et al. Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain. Published online January 8 2016