British scientists explore drug target against neurodegeneration in mice
19 December 2016
The Journal of Clinical Investigation: M1 muscarinic allosteric modulators slow prion neurodegeneration and restore memory loss.
A team of researchers from the UK, US and Australia has discovered that chemicals to mimic the action of a chemical messenger called acetylcholine could restore memory loss and prolong life in mice bred to develop a progressive neurodegenerative disease. The findings identify a target called the M1 muscarinic acetylcholine receptor (M1 mAChR) that could be used to develop new treatments for diseases like Alzheimer’s disease. The results are published on 19 December in The Journal of Clinical Investigation.
Acetylcholine is a chemical messenger that allows nerve cells in the brain to communicate – key to maintaining brain function and cognition. In diseases like Alzheimer’s, acetylcholine levels start to fall and current licensed drugs for the disease act to boost levels of the messenger in an attempt to improve symptoms like memory loss. Although these existing drugs can be effective for some people, they do not work for everyone and their benefits wear off after time. To look for a more effective way to benefit those with the disease, researchers focused on one protein that acetylcholine binds to, called M1 AChR. By using drugs to artificially activate this protein, they hoped to mimic the positive effects on memory and thinking that are lost in diseases like Alzheimer’s.
To do this, they used mice bred to show a progressive loss of nerve cells due to the abnormal build-up and spread of proteins in the brain. These mice mimicked so-called ‘prion diseases’ like Creutzfeldt-Jakob disease (CJD), but the loss of nerve cells can also act as a more simple representation of what ultimately happens in the brain in diseases like Alzheimer’s. These mice also experienced a fall in levels of the acetylcholine messenger seen in Alzheimer’s, and performed poorly on particular tests of learning and memory.
The team treated the mice with several different chemicals all designed to mimic or enhance the activity of acetylcholine at the muscarinic acetylcholine receptor M1. The chemicals, called xanomeline, BQCA and BQZ-12, were all able to restore memory symptoms in the mice. Daily doses of BQCA also increased the survival of the mice compared to untreated mice, and it took longer for their disease to take hold. The team suggests that drugs targeting the M1 AchR could hold potential not only for treating symptoms of diseases like Alzheimer’s, but potentially delaying its progression.
Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said:
“These kinds of detailed early studies in mice are important for exploring potential drug targets to follow up in the search for new treatments for diseases like Alzheimer’s. Efforts to target this particular protein have been ongoing for several years but have hit hurdles around safety that could limit their use in people. One encouraging aspect of this study is that the chemicals were able to extend the lives of mice, suggesting that it’s an area of drug discovery where efforts should be boosted. The long wait for new Alzheimer’s treatments illustrates the challenge in developing new drugs against the disease and any potential new approach would have to be safe and effective in people.
“It’s almost 15 years since the last drug for Alzheimer’s became available and it’s promising to see new avenues being explored. To have the best chance of ending the long wait for new treatments, researchers will need to follow as many leads as possible, creating a diverse pipeline of potential targets for further development. Not all of these new drugs will be successful, but it only takes one success to change the lives of people with dementia in the future.”