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The aggregation of certain proteins is linked to the progression of Alzheimer’s disease and a group of scientist publishing in the journal Science Advances have reported their use of an anticancer drug to prevent this build up in a worm model organism.
Dr Mark Dallas, Lecturer in Cellular and Molecular Neuroscience at the University of Reading, said:
“This research looks into how using a drug, which is already approved for treating cancer, could interfere with the build-up of the toxic amyloid beta proteins in the brain, thought to cause Alzheimer’s.
“The scientists are suggesting this could be used as a preventative drug to stop someone from getting Alzheimer’s, in the same way people take statins to prevent heart disease. This highlights the critical nature of when to intervene in the disease process. The results show that once the disease was evident, the drug no longer showed any benefits. This underlines that future treatments are more likely to work if the disease is caught in the very early stages, or even before any signs are detected.
“Previous research using this drug, bexarotene, in animal tests has produced mixed results for Alzheimer’s. There was also a clinical trial in humans that failed to show any benefit to patients.
“Unfortunately, 99% of drugs developed to fight Alzheimer’s go on to fail. It is therefore too early to tell if this study will be translated into the development of a new drug that can effectively target amyloid beta and hence prevent someone from developing Alzheimer’s disease.”
Prof. John Hardy, Professor of Neuroscience, UCL, said:
“This is a very curious paper. A paper reporting the drug tested in this work was reported to help in mouse models of the disease in 2012 but then a series of reports came out to say there were errors in the original report. This work suggests again this drug may be helpful but suggests a totally different mechanism from the first report. Clearly, this work will cause a stir, but equally clearly there will be those who suspect the work is correct and those who suspect it is wrong. It is too early to predict whether this will eventually lead to therapy, particularly in view of the controversy surrounding the earlier studies.”
Dr Doug Brown, Director of Research and Development at Alzheimer’s Society, said:
“Previous studies looking at bexarotene, a cancer drug, to clear away amyloid plaques from the brain in Alzheimer’s disease, have not been successful in people. This research in worms suggests that the drug should now be tested in the very early stages of Alzheimer’s as it may stop amyloid plaques from forming in the first place.
“Bexarotene has many side effects when used to treat lymphoma, such as skin complaints, headaches, and sickness, and we would also need to be sure that it’s safe for people with Alzheimer’s to take. It’s early days for bexarotene and certainly too soon to tell whether it could be used in a similar preventative way to statins for heart disease.
“We haven’t found any new drugs for dementia in over 10 years, and repurposing drugs that already work for other conditions could provide us with a shortcut to new dementia treatments. Our Drug Discovery Programme is currently funding a range of trials looking at repurposing drugs for other conditions, such as diabetes and arthritis.”
Dr Rosa Sancho, Head of Research at Alzheimer’s Research UK, said:
“We know that the accumulation of amyloid is a hallmark feature of Alzheimer’s and that drugs to halt this build-up could help protect nerve cells from damage and death. A recent clinical trial of bexarotene in people with Alzheimer’s was not successful, but this new work in worms suggests the drug may need to be given very early in the disease. We will now need to see whether this new preventative approach could halt the earliest biological events in Alzheimer’s and keep damage at bay in further animal and human studies.
“Bexarotene hit the headlines in 2012 after a study in mice suggested the drug could clear amyloid from the brain, but further studies to reproduce this finding have been mixed. This early research in worms suggests that bexarotene could act earlier in the process to interfere with amyloid build-up, but it is too soon to conclude that the drug could be used as a way to prevent Alzheimer’s and whether this would be a safe approach in healthy people. Bexarotene is the subject of a lot of scientific interest as researchers seek to understand why studies have yielded differing results and it’s important that scientists fully examine how this drug works to inform any future clinical trials in Alzheimer’s.
“Alzheimer’s Research UK is committed to finding effective treatments for the 850,000 people in the country living with dementia. Our £30 million Drug Discovery Alliance will take the most promising ideas and accelerate the hunt for new medicines in the clinic. We know that increased investment in dementia research is the only way to tackle this huge medical challenge.”
Further references from John Hardy:
Science. 2012 Mar 23;335(6075):1503-6. doi: 10.1126/science.1217697. Epub 2012 Feb 9.
ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models.
Cramer PE1, Cirrito JR, Wesson DW, Lee CY, Karlo JC, Zinn AE, Casali BT, Restivo JL, Goebel WD, James MJ, Brunden KR, Wilson DA, Landreth GE.
Abstract: Alzheimer’s disease (AD) is associated with impaired clearance of β-amyloid (Aβ) from the brain, a process normally facilitated by apolipoprotein E (apoE). ApoE expression is transcriptionally induced through the action of the nuclear receptors peroxisome proliferator-activated receptor gamma and liver X receptors in coordination with retinoid X receptors (RXRs). Oral administration of the RXR agonist bexarotene to a mouse model of AD resulted in enhanced clearance of soluble Aβ within hours in an apoE-dependent manner. Aβ plaque area was reduced more than 50% within just 72 hours. Furthermore, bexarotene stimulated the rapid reversal of cognitive, social, and olfactory deficits and improved neural circuit function. Thus, RXR activation stimulates physiological Aβ clearance mechanisms, resulting in the rapid reversal of a broad range of Aβ-induced deficits.
Comment in Medicine. Old drug, new hope for Alzheimer’s disease. [Science. 2012]
Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. [Science. 2013]
Response to comments on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. [Science. 2013]
Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. [Science. 2013]
Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. [Science. 2013]
Neurodegenerative disease: RXR agonist reverses Alzheimer’s disease. [Nat Rev Drug Discov. 2012]
Comment on “ApoE-directed therapeutics rapidly clear β-amyloid and reverse deficits in AD mouse models”. [Science. 2013]
‘An anticancer drug suppresses the primary nucleation reaction that produces the toxic Ab42 aggregates linked with Alzheimer’s disease’ by Habchi et al. published in Science Advances on Friday 12th February.
Declared interests
Dr Mark Dallas: Received funding from ARUK and is Neuroscience Theme Lead, The Physiological Society
Prof. John Hardy: Consults on Alzheimer therapy for Eisai pharmaceuticals
Dr Doug Brown: No conflicts of interest
Dr Rosa Sancho: No conflicts of interest