Alzheimer’s disease is a neurodegenerative disorder and is the most common cause of dementia. The degradation of brain matter leads to symptoms including memory loss and difficulties with thinking, problem-solving or language. As Alzheimer’s disease is a progressive disorder the symptoms gradually get worse over time 1. In 2015 it was estimated that 46.8 million people were living with dementia 2. Thus drug development to reduce or stop the progression of Alzheimer’s disease is heavily invested in as there is no effective treatment.
It has been shown that an overactive immune system can play an important role in Alzheimer’s disease. Within the immune system particularly the inflammasome has been implicated in Alzheimer’s disease. The inflammasome is a large bundle of proteins which are responsible for producing proinflammatory cytokines in cells. The cytokines then promote inflammation in the brain which causes can worsen Alzheimer’s disease.
The plan – to inhibit the inflammasome complex to improve the outcomes for people living with Alzheimer’s disease. Designing new drugs can take 20 years to get into clinic and cost 1.6 billion dollars in the process. Dr David Brough, leading the study employed the strategy of ‘repurposing’ to discover drugs for Alzheimer’s disease i.e. using a drug already approved in the market to treat another disease. This involved testing drugs from a large class of non-steroidal anti-inflammatory drugs (NSAIDs) to determine if they could inhibit the inflammasome and therefore have potential therapeutic benefit in Alzheimer’s disease.
From screening many NSAIDs for their activity on immune cells, mefenamic acid was identified as having the ability to inhibit the inflammasome and prevent the release of inflammatory cytokines (figure a). This is a drug mainly prescribed for the treatment of period pain. The next step was to identify how the drug was working. It is understood that ion channels on the cell surface may be involved in inflammasome activation and the proposed mode of action of mefenamic acid was that it inhibits particular ion channels. During this study the target was identified as a chloride ion channel called the volume-regulated anion channel (VRAC).
In order to make the link between these exciting initial findings and the effectiveness of mefenamic acid at treating Alzheimer’s disease animal models were utilised. Firstly a rat model of amyloid-beta induced memory deficits was used. Amyloid beta plaques are known to be a major hallmark of Alzheimer’s disease and the injection of the protein into rat brains results in permanent memory deficits. From the novel object recognition test it was found that mefenamic acid protected the rats from these memory deficits.
The next model that was studied was a mouse model of expressed genes found in the humans with the genetic form of Alzheimer’s disease. In this model the symptoms are progressive, starting from when the mice are 14 months old (simulating the human disorder). Using a water maze based task it was determined that mefanamic acid was able to reverse the memory deficits observed in placebo treated mice. Additionally there was much inflammation in the brains of placebo treated mice but no inflammation in the case of mefenamic acid treated mice.
In conclusion from this study we can see that Alzheimer’s disease is a debilitating progressive disorder which is a huge global concern. There is strong evidence that overactivity of the immune system, particularly the inflammasome protein complex is involved. Testing NSAIDs led to the identification of mefenamic acid which inhibits the inflammasome by blocking the VRAC ion channel and it was effective in at eliminating memory deficits associated with Alzheimer’s disease in mouse and rat models. The group is planning to progress to clinical trials, and since the drug is already known and approved there is no requirement for a safety testing stage.
Daniels, M.J.D., Rivers-Auty, J., Schilling, T., Spencer, N.G., Watremez, W., Fasolino, V., Booth, S.J., White, C.S., Baldwin, A.G., Freeman, S., Wong, R., Latta, C., Yu, S., Jackson, J., Fischer, N., Koziel, V., Pillot, T., Bagnall, J., Allan, S.M., Paszek, P., Galea, J., Harte, M.K., Eder, C., Lawrence, C.B. and Brough, D. 2016. Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models. Nature Communications. 7, p12504.
1 Alzheimer’s Society Website https://www.alzheimers.org.uk/
2 Alzheimer’s Disease International Website https://www.alz.co.uk/research/statistics
Blog written by Rachael Besser