Blimey it’s been a long time since I’ve managed to get a blog out! Part of the reason for my lack of input lately has been the madness surrounding publishing some of our research. Our paper, titled “Fenamate NSAIDs inhibit the NLRP3 inflammasome and protect against Alzheimer’s disease in rodent models” was published in the journal Nature Communications last week and I thought this would be a good opportunity to add my own voice to the current media storm surrounding this research (no – we haven’t cured Alzheimer’s disease) and give a bit of an insight in to what went on.
A large focus of our lab is on finding treatments for Alzheimer’s disease. Alzheimer’s is a chronic, progressive brain disorder that involves the literal degradation of brain tissue. This results in symptoms such as changing emotions, loss of spatial awareness and, perhaps the most devastating, loss of memory. Alzheimer’s disease currently affects 26 million people worldwide with this number ever increasing. Due to this, huge investment is being poured into drug development to slow or halt the progression yet there still remains no truly effective treatment.
Our lab group are particularly interested in AD because we specialise in the role of the immune system in the brain and research suggests that an overactive immune system may play an important role in Alzheimer’s disease. One particular part of that immune system that has recently been heavily implicated in Alzheimer’s is something called an inflammasome. The inflammasome is a large bundle of proteins which forms a kind of machine within cells whose job it is to produce proinflammatory cytokines. These cytokines go on to promote inflammation in the brain which can worsen Alzheimer’s disease.
OK so we have a plan – inhibit the inflammasome complex in the hope of improving outcomes for people living with Alzheimer’s disease. But how do we do this? We could design new drugs (something our lab is involved in right now) but to get a new drug into the clinic can take around 20 years and cost around 1.6 billion dollars. Another quicker, cheaper option is to do something called ‘repurposing’ which involves using a drug already approved and on the market and using it to treat another disease. It was here that our lab head Dr David Brough came up with the idea to test a number of drugs from a large class called non-steroidal anti-inflammatory drugs (NSAIDs) to see if they could inhibit the inflammasome and thus potentially be used in Alzheimer’s disease. This was the project I was tasked with in my first week of PhD life nearly two years ago, something you’ll see I had a huge amount of help with along the way especially from a fantastic postdoc in our lab Dr. Jack Rivers-Auty with whom I share first authorship on the paper.
We began by testing a number of these NSAIDs on immune cells cultured in a flask. This gave us the important opportunity to screen a large number of drugs without unnecessary use of animals. When we ran these screens we had a bit of a surprise. The more famous NSAIDs such as ibuprofen (Nurofen) had no effect. However, one drug, mefenamic acid, was able to inhibit the inflammasome and prevent release of inflammatory cytokines. Mefenamic acid is only available by prescription and is given largely to treat period pains however has also been used for most forms of mild to moderate pain.
We next worked to discover how exactly these drugs were working. Research suggests that ion channels on the cell surface play an important role in inflammasome activation and that mefenamic acid may inhibit some forms of ion channels. To better understand this we formed a collaboration with a London-based research group led by Dr. Claudia Eder – an expert in electrophysiology (researching ion channels). It was with the help of Dr. Eder’s lab that we identified the target of the drugs as a chloride channel called the volume-regulated anion channel (VRAC).
Do the drugs work in living systems?
Now we had the drug and the mechanism but we still don’t know anything about whether our drug will be effective in treating Alzheimer’s disease. So we began to look at animal models. The first model we chose was a rat model of amyloid-beta induced memory deficits. Build-up of amyloid-beta is thought to be one of the main causes for Alzheimer’s disease and, if injected into the brain of rats, it causes permanent memory deficits. As part of a collaboration with Dr. Mike Harte’s lab here at Manchester, we injected a group of rats with mefenamic acid or placebo and showed that those which received the drug were completely protected from memory deficits, something you can test by assessing the ability of rats to recognise a novel object vs an object it has seen before.
We then moved to look at the effect of the drug in a genetic mouse model of Alzheimer’s disease. These mice have been altered to express some of the genes found in humans with the genetic form of Alzheimer’s disease and will develop memory deficits at around 14 months of age. We took mice at this very age (thus attempting to model what would happen if a human began taking the drug just as the symptoms of Alzheimer’s were beginning) and treated them with mefenamic acid or placebo to see the effects. What we found was that mice given mefenamic acid were completely normal whereas those without the drug displayed severe memory deficits (this time measured by their ability to remember the location of a platform in a water maze). We also found that the brain of the placebo mice displayed signs of intense inflammation. The brains of the drug-treated mice however remained completely normal.
So to conclude, Alzheimer’s disease is a terrible and currently incurable condition which we believe to be partially caused by an overactive immune system – specifically over-activity of a protein complex called an inflammasome. We tested a number of currently available drugs and found that one, mefenamic acid was able to inhibit the inflammasome. It did this by blocking an ion channel called VRAC and we found the drug effective in both mouse and rat models of Alzheimer’s-like memory deficits.
So what’s the next step? We are hoping to begin to move mefenamic acid to clinical trials to really see if it could work in humans. Luckily, because the drug is already known and approved we can skip the safety testing stage of the clinical trial process. Unfortunately however, clinical trials remain extremely expensive and, as mefenamic is off patent and can no longer be sold for profit, gaining funding through pharmaceutical companies is nigh-on impossible. This means we are relying on donations to fantastic charities such as Alzheimer’s Society and Alzheimer’s Research UK in order to progress this study forward.
A lot of work is needed and it will still be a while before we have results in people currently living with Alzheimer’s disease, but this remains an exciting step and we can only hope that this, or something out there being tested by the huge number of researchers working on Alzheimer’s, will go some way to treating, or better, stopping this horrible disease.