Psoriasis drug could hold key to dementia treatment
BBC News reports that, "drugs used to calm inflammation in psoriasis may also help to combat the effects of Alzheimer's disease, a study on mice suggests."
Alzheimer's disease is a type of dementia, a condition characterised by the loss of healthy brain cells and the formation of abnormal deposits of proteins ('plaques') and fibres inside the brain.
The news is based on a study that found that proteins released by the immune system (IL-12 and IL-23) that are associated with inflammation were found in high levels in the brains of mice genetically programmed to develop a disease similar to Alzheimer's (a 'mouse model' of Alzheimer's).
They used two methods to lower the levels of IL-12 and IL-23 in the mouse model of Alzheimer's:
- deleting the genes that carry the instructions for making IL-12 and IL-23
- treating the mice with an antibody that blocks the effects of IL-12 and IL-23
Both methods were found to reduce the formation of plaques, and the antibody treatment could reverse some of the behavioural problems seen in the mouse model of Alzheimer's.
This finding has generated particular interest because ustekinumab, a drug which blocks the effects of IL-12 and IL-23, is already used to treat psoriasis in humans.
Because safety data already exists for the use of this drug treating people with psoriasis, it may mean that human trials using it to treat Alzheimer's disease could happen sooner than for a completely new drug.
However, it is likely that this is still a way off, with more animal research needed first to support the possible effectiveness and safety of the treatment for Alzheimer's.
Where did the story come from?
The study was carried out by researchers from the University of Zürich in Switzerland and other universities in Germany. It was funded by Deutsche Forschungsgemeinschaft, the Swiss National Science Foundation, the Koetzer Foundation, NeuroCure, the US National Institutes of Health and the European Union.
Two of the authors hold a patent application for the use of modulators of IL-12 and IL-23 for the prevention or treatment of Alzheimer's disease (the approach being tested in the current study).
The study was published in the peer-reviewed journal Nature Medicine.
The BBC covers this research well, stating clearly in its headline that this study is in mice.
The reporting also includes quotes that stress the early nature of this study, the possibility that the results may not apply in humans, and the need for further clinical trials.
What kind of research was this?
This animal research investigated the role of inflammation in Alzheimer's disease using a mouse model of the disease.
A characteristic feature of Alzheimer's disease is the accumulation of a protein called amyloid beta, which forms deposits in the brain called plaques.
These plaques are then surrounded by immune system cells called microglia. These cells secrete chemicals that promote inflammation, which is part of the immune system's normal response to tissue injury.
Previous research has found that chemicals associated with inflammation are found in higher levels in the local area of plaques.
The current study looked at the role of IL-12 and IL-23 – two chemicals produced by the microglia that are related to inflammation – in the formation of amyloid beta deposits.
They did this by deleting the genes for 'subunits' of IL-12 and IL-23 and seeing the effect on mice.
The researchers then tested the effectiveness of an antibody against p40, a subunit of both IL-12 and IL-23.
A drug containing an antibody against p40 (ustekinumab) is already recommended by the National Institute for Health and Clinical Excellence (NICE) for the treatment of severe psoriasis that has not responded to standard therapy.
An animal study is ideal for this early-stage research. However, future studies will be required to determine whether the results are applicable for humans.
What did the research involve?
The researchers looked at the levels of IL-12 and IL-23 in a mouse model of Alzheimer's disease.
They then crossed the mouse model of Alzheimer's disease with mice that lacked p40, or just lacked IL-12 or IL-23.
The brains of the offspring mice were compared to the original mouse model of Alzheimer's disease at 120 days – when deposits of amyloid beta can usually already be seen in the brain of mice – and again at 250 days.
The researchers then looked at the effect of blocking p40 using an antibody to see if this would affect amyloid beta levels in the brain. Antibodies against p40 would target both IL-12 and IL-23.
The antibody was injected into the abdominal cavity of the mice with the mouse model of Alzheimer's disease, starting at the age of 28 days and then twice a week until the age of 120 days, at which point they looked at their brains.
They also carried out experiments to see whether the antibodies against p40 would have any effect on behaviour in older mice with established amyloid beta plaques.
Pumps that released the p40 antibody directly into the brain were placed in the brains of 190-day-old mice for 60 days.
By this age, the mice would usually be showing mild behavioural abnormalities in specific tests such as mazes, behaviour in an open space and the ability to recognise new objects. The researchers carried out these tests on the following three groups:
- anti-p40 antibody treated Alzheimer's model mice
- Alzheimer's model mice treated with a control antibody
- normal mice
Finally, the researchers measured the concentration of p40 in the fluid surrounding the brain and spine of humans with Alzheimer's disease, as well as humans without the disease.
They then looked at whether the level of p40 was related to a person's cognitive performance.
What were the basic results?
The researchers found that the microglia in the brains of a mouse model of Alzheimer's disease were making higher levels of both IL-12 and IL-23 than the microglia in normal mice.
When the mouse model of Alzheimer's disease was crossed with mice lacking either p40 or just IL-12 or IL-23, the offspring mice had much lower levels of amyloid beta deposits in their brains at 120 days than the original mouse model.
The effect was greatest in the mice lacking p40, which had 63% less amyloid beta deposits in their brains at 120 days than the original mouse model.
A significant reduction was also seen when the mice were aged 250 days, suggesting that amyloid formation had not just been delayed.
Injecting the p40 antibody into the abdominal cavity of mice with the mouse model of Alzheimer's disease reduced amyloid beta deposits in the brain by 31%. However, the effects varied between the different mice.
If the antibody was pumped directly into the brains of older Alzheimer's model mice, they performed similarly to normal mice in the maze test and recognition of new objects test.
The antibody did not appear to have reduced the existing plaques in these mice, but they had less soluble amyloid beta circulating in their brains.
The researchers found that the level of p40 in the fluid surrounding the brain and spine of subjects with Alzheimer's disease and those without the disease (both in mice and humans) was related to their cognitive performance.
People who had higher levels of p40 had lower cognitive performance.
How did the researchers interpret the results?
The researchers concluded that their results show evidence that the the immune system plays a role in the development of Alzheimer's disease.
They say that it is not clear if the immune system contributes towards causing the disease, but it can influence disease progression.
The researchers also say that p40 antibodies are an ideal candidate for clinical trials, as they have already been tested in psoriasis and are approved in the US.
They suggest that initial prevention or treatment trials could be carried out in people with mild cognitive impairment or Alzheimer's disease that is not yet causing symptoms.
Conclusion
The current study identifies that the immune system proteins IL-12 and IL-23 potentially play a role in Alzheimer's disease.
It also suggests that blocking these proteins with antibodies against a common component called p40 could reduce the formation of amyloid beta plaque. This in turn reversed some of the behavioural problems associated with these plaques, as seen in a mouse model of Alzheimer's disease.
As the current study was in mice, the results may not apply to humans. The researchers did a small assessment in humans which did support the possibility that the findings may apply (specifically a possible role of p40), but more research will be needed to confirm this.
As the authors note, antibodies against p40 have been used in humans to treat psoriasis. NICE already recommends a treatment containing an antibody against p40 (ustekinumab) for the treatment of severe psoriasis that has not responded to standard therapy.
Since some safety data for this drug in humans already exists, it may mean that human trials testing the treatment in Alzheimer's disease could occur sooner than if the drug had never been tried in humans.
However, it is likely that these are still a way off, with more animal research needed first to support the possible effectiveness of the treatment.
