Publishing in Science Translational Medicine researchers claimed a drug targeting Tau – a protein that builds up in the brains of people with some neurodegenerative disorders, including Alzheimer’s – prevented loss of brain cells in experimental animals.
Prof. Gordon Wilcock, Emeritus Professor of Geratology, University of Oxford, said:
“This is important work as it strengthens the possibility that reducing the abnormal tau pathology that occurs in several neurological diseases, including Alzheimer’s disease, may be beneficial. Injection of the treatment, known as ASOs, into one of the hollow spaces in the brains of mice bred to develop tau pathology not only protected brain cells, but also reduced the spread of the pathology within the brain, and reversed pre-existing pathological changes. This improved behavioural deficits and extended survival and could lead to treatments for a number of neurological diseases where tau is abnormal.
“However, results in animal models are a long way from treating humans. Not only will the treatment’s safety have to be established before clinical trials can take place, but also an alternative and more practical way of delivering this treatment to the brain is needed. It will encourage the development of other ways to reduce tau pathology that are easier to administer.
!It is exciting to think that this may lead to a treatment that tackles the tangles in AD brain cells, and could complement the treatments being developed to remove the other abnormality in Alzheimer’s disease, the amyloid protein, such that one day we may be able to target both the main abnormalities that occur in the brain in this disease.”
Dr Christopher Morris, Senior Lecturer, Newcastle University’s Institute of Neuroscience, said:
“This is an interesting paper and certainly at first glance seems to suggest that there could be a treatment for Alzheimer’s disease (AD) and frontotemporal dementia (FTD). In AD and FTD neurofibrillary tangles (NFT) composed of abnormal Tau protein accumulate in nerve cells and lead to eventual nerve cell death and clinical symptoms. The paper reports the use of an antisense oligonucleotide (ASO) specifically directed at tau to reduce the production of tau messenger RNA and consequently tau protein. The authors have used a mouse which over-produces a mutant form of human tau (found in rare FTD families) and which has symptoms of motor neurone death (not dissimilar to motor neurone disease) and which has behavioural problems which might indicate some memory problems. Importantly these mice produce structures in their brains which look similar to NFT found in AD and FTD. Treating the mice with the ASO appeared to be safe and because it reduced the production of human tau by these mice, it reduced the levels of pathology and NFTs and consequently any behavioural and motor problems. What was interesting was that when mice were treated with the ASO at a time when they should be starting to show early NFT type changes, they didn’t decline as rapidly as they would have done normally (although it didn’t stop the decline, merely slowed it). This might suggest that the use of ASO would only delay progress of the disease in people with AD or FTD. What the authors haven’t done however is to undertake a formal test of memory (only nest-building behaviour) so how the ASO treatment might affect memory is not clear.
“One caveat to the study is that the mouse model has very high level expression of the human tau gene which isn’t seen in people with Alzheimer’s disease or in frontotemporal dementia. The compound ASO only reduces the human tau that is over-expressed and not the normal tau gene which the mice still have and consequently the mice don’t get the pathology which causes their physical and behavioural problems. How the ASO would affect a normal mouse if given for very long periods of time isn’t clear since there is some evidence to suggest that getting rid of tau altogether affects how nerve cells function (although some more recent work indicates that this might not be the case). Some studies even suggest that getting rid of tau might lead to memory deficits which would be counterproductive. The work treating normal monkeys with the ASO compound only provides part of an answer in that the short term administration seems to show that it works in reducing tau production and appears safe. Only longer tests, perhaps over years in monkeys, will tell if the treatment might be safe to be applied in people over the long periods of time which will be needed to treat someone with AD or FTD and this is something that the authors are cautiously advising. It would also be relevant here to see how the ASO treatment affects memory in monkeys since, if reducing tau is bad for memory, this would be something that would be needed in any preclinical tests before moving to trials in man.
“What shows potential is the fact that the use of these ASO compounds (Spinraza) has been approved for clinical use in the United States in spinal muscular atrophy (SMA) a rare condition of children and young adults. While the compound has to be directly injected into the cerebrospinal fluid which in itself has inherent problems, it does indicate that it should be possible to use this route to treat people with AD or FTD and could be extended to other disorders involving tau including progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS).”
Dr Tara Spires-Jones, Interim Director, Centre for Cognitive and Neural Systems, University of Edinburgh, said:
“This is a very promising study showing that lowering levels of tau is beneficial a mouse model of frontotemporal dementia.
“Tau is one of the proteins that builds up in the brains of people with Alzheimer’s disease and several other diseases called tauopathies. The experiments demonstrate that in mice, reducing the amount of tau prevented loss of brain cells, which bodes well for preventing further decline in people with tauopathies including Alzheimer’s disease. The science here is sound, but there is a long way to go to before we will know whether this will help people living with Alzheimer’s and other diseases with tau accumulation.
“One caution is that the group sizes are small, from 3-10 mice per treatment group; another caution is that this is a single model of a genetic form of frontotemporal dementia with Parkinsonism. It will be important to replicate these promising results in other models with larger group sizes to make sure the effects are robust before taking this type of treatment to clinical trials in people.”
Prof. Rob Howard, Professor of Old Age Psychiatry, UCL, said:
“This is an exciting and potentially important finding. Abnormal tau protein deposition is responsible for neurofibrillary tangles – a hallmark abnormality seen in the brains of patients with neurodegenerative disorders including Alzheimer’s disease. The more abnormal tau deposited in the brain – the more severe the level of dementia.
“This work involved disrupting the signalling of a mutation in a human gene that results in brain deposition of tau and that had been inserted into a mouse. Such mice deposit abnormal tau in their brains as they age and develop motor and cognitive abnormalities that could be described as ‘mouse dementia’. The experimental treatment stopped tau appearing in the brains of the mice as they aged and even reversed the appearance of tau in older mice. The brains of treated animals didn’t shrink as fast, they lived longer and were able to build themselves complete and comfortable nests for longer.
“Putting aside concerns that this demonstration was in an artificial mouse model and that we don’t yet know which genes cause common dementias like Alzheimer’s disease, it is easy to see how this approach could lead to meaningful treatments for those rarer neurodegenerative disorders and familial Alzheimer’s disease where we do have single responsible genes. Obviously, several years of safety testing and efficacy trials in humans have to be crossed, but there is definite potential for this approach to deliver a treatment for people with some of the rarer dementias within the next decade. I don’t believe this approach will be quickly applicable to cases of the more usual, sporadic and late-onset Alzheimer’s disease.”
Prof. John Hardy, Professor of Neuroscience, UCL, said:
“This is an interesting paper which takes forward the idea that knocking down of genes causing neurodegenerative diseases will help in treating neurodegenerative diseases. While this work is of interest, it is some distance from clinical practice. In the mice used in these experiments, human mutant tau was artificially over-expressed – this give the mice a mimic of the human disease as has been known for 20 years – then they reduced the amount of the human protein by this knockdown experiment and the mice got better. This is very different from Alzheimer’s disease where the tau is neither mutant nor artificially over-expressed.”
Dr David Reynolds, Chief Scientific Officer at Alzheimer’s Research UK, said:
“This robust study presents an interesting and potentially powerful approach to target tau build-up in the brain. Recent disappointing results from clinical trials using anti-amyloid therapies highlight the importance of researching other areas of the underlying biology of Alzheimer’s disease in the search for new treatments. While several anti-tau drug approaches are already in testing in people, animal studies like this can provide promising new leads to develop towards clinical trials. Tau protein is an attractive target for the development of new treatments for dementia, due to its central role in several neurodegenerative diseases including Alzheimer’s.
“It is important to remember that all new drugs need to be thoroughly tested in people to make sure they’re safe and effective. We’re already seeing encouraging results with this RNA approach in several other rare inherited diseases. While we don’t yet know how safe and effective such a therapy would be in Alzheimer’s, this data provides a strong case that it could be a valid therapeutic approach. It is vital we continue to invest in research to understand the biology of different forms of dementias to develop the drugs that are so desperately needed by the 850,000 people living with the condition in the UK.”
* ‘Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy’ by DeVos et al. published in Science Translational Medicine on Wednesday 25th January.
Prof. Wilcock: “I am a member of the Scientific Advisory Board to TauRx, a company trialing an anti-tau treatment strategy for Alzheimer’s disease. I have also received honoraria from other companies in relation to the development and evaluation of other drugs for Alzheimer’s Disease.”
Dr Morris: “I have received funding from Alzheimer’s Society, Medical Research Council. I assist with local Progressive Supranuclear Palsy support group, am a member of the British Toxicology Society and am Chair of the Peer Review Panel of the Parkinson’s UK and Multiple Sclerosis UK tissue bank. I have no financial interests.”
Dr Spires-Jones: “I have no financial conflicts interest with this paper. I am employed by the University of Edinburgh and am a member of the Grant Review Board for Alzheimer’s Research UK.”
Prof. Howard: “No conflicts.”
Prof. Hardy: “I consult for Ceracuity Pharma”
Dr Reynolds: “As a former employee I own shares in Merck Inc and Pfizer.”