Scientists from the University of Cambridge have developed a method to boost the brain’s self-clearing mechanism, known as autophagy, in mice suffering from Huntington’s disease and dementia. They’ve discovered that an already existing HIV medication, maraviroc, has the ability to obstruct a specific component (CCR5) that disrupts autophagy, consequently lessening the harmful protein accumulation, potentially delaying memory loss.
An HIV drug has been demonstrated to shield against the accumulation of proteins associated with dementia in the brains of mice.
Cambridge researchers have elucidated the brain’s diminished ability to remove harmful proteins in conditions such as Huntington’s disease and other dementias. In a mice study, they revealed that a repurposed HIV medication was able to rejuvenate this essential function, thereby inhibiting the perilous buildup and slowing the disease’s progression.
A typical feature of neurodegenerative diseases like Huntington’s and various dementias is the formation of clusters in the brain, termed aggregates, of misfolded proteins, like huntingtin and tau. These aggregates lead to the deterioration and eventual death of brain cells, thereby precipitating symptoms.
According to David Rubinsztein, “We’re very excited about these findings because we’ve not just found a new mechanism of how our microglia hasten neurodegeneration, we’ve also shown this can be interrupted.”
Autophagy is one of the ways our bodies dispose of toxic materials. It is a cellular process that engulfs unwanted substances, breaks them down, and discards them. However, this mechanism is dysfunctional in neurodegenerative diseases, rendering the body incapable of eliminating misfolded proteins.
A research team from the Cambridge Institute for Medical Research and the UK Dementia Research Institute at the University of Cambridge has unveiled a process that hinders autophagy’s proper functioning in the brains of mice with Huntington’s disease and a form of dementia. Importantly, they have discovered a drug that helps restore this vital function.
The researchers conducted their experiments using mice genetically modified to develop forms of Huntington’s disease or a type of dementia characterized by tau protein buildup.
The brain and central nervous system contain specialist immune cells, known as microglia, tasked with guarding against harmful and toxic materials. In neurodegenerative diseases, microglia become active in a way that impairs autophagy.
The team demonstrated in mice that neurodegenerative diseases prompt microglia to release a group of molecules which activate a switch on the surface of cells. When this switch, known as CCR5, is activated, it impairs autophagy, thereby disrupting the brain’s ability to dispose of toxic proteins. These proteins then aggregate and cause irreversible brain damage, with the toxic proteins also creating a feedback loop leading to accelerated aggregate buildup.
Professor David Rubinsztein, the study’s senior author, noted: “The microglia start releasing these chemicals long before any physical symptoms of the disease appear. If we’re going to find effective treatments for diseases such as Huntington’s and dementia, these treatments will likely need to begin before an individual starts showing symptoms.”
Mice bred to inhibit the action of CCR5 demonstrated protection against the buildup of misfolded huntingtin and tau, resulting in fewer brain toxic aggregates compared to control mice.
These findings hint at potential methods to slow or prevent this buildup in humans. The CCR5 switch is not just exploited by neurodegenerative diseases, it’s also utilized by HIV as an entry point into our cells. Maraviroc, a drug approved in 2007 for HIV treatment, inhibits CCR5.
The researchers treated mice with Huntington’s disease using maraviroc for four weeks, starting when the mice were two months old. Upon examination of the mice’s brains, they found a significant reduction in huntingtin aggregates compared to untreated mice. However, it was too early to ascertain if the drug impacted the mice’s symptoms, as Huntington’s disease only presents as mild symptoms by 12 weeks even without treatment.
A similar effect was observed in mice with dementia. The drug not only reduced the amount of tau aggregates but also decelerated the loss of brain cells. The treated mice outperformed untreated mice in an object recognition test, suggesting the drug delayed memory loss.
Rubinsztein further stated, “We’re very excited about these findings because we’ve not just found a new mechanism of how our microglia hasten neurodegeneration, we’ve also shown this can be interrupted, potentially even with an existing, safe treatment.
“Maraviroc might not be the ultimate solution, but it shows a possible direction. While developing this drug for HIV treatment, several other candidates failed because they were not effective against HIV. We might find that one of these could effectively prevent neurodegenerative diseases in humans.”
The study titled “Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration” by Beatrice Paola Festa, Farah H. Siddiqi, Maria Jimenez-Sanchez, Hyeran Won, Matea Rob Alvin Djajadikerta, Eleanna Stamatakou, and David C. Rubinsztein, was published on 26 April 2023 in Neuron. DOI: 10.1016/j.neuron.2023.04.006
The research received support from Alzheimer’s Research UK, the UK Dementia Research Institute, Alzheimer’s Society, Tau Consortium, Cambridge Centre for Parkinson-Plus, Wellcome, and the European Union’s Horizon 2020 research and innovation program.
Table of Contents
Frequently Asked Questions (FAQs) about HIV drug Maraviroc
How was the HIV drug Maraviroc used in the research?
The University of Cambridge researchers used Maraviroc, an HIV drug, to treat mice genetically altered to develop forms of Huntington’s disease or a type of dementia. The treatment showed significant reduction in harmful protein aggregates in the brain.
What is autophagy and how does it relate to this research?
Autophagy is a cellular process that gets rid of unwanted substances by engulfing and breaking them down. In this study, researchers discovered that in Huntington’s disease and certain types of dementia, this process doesn’t work properly, leading to the accumulation of harmful proteins in the brain. An HIV drug, Maraviroc, was found to help restore this vital function.
What is the CCR5 switch?
CCR5 is a cellular switch that, when activated in neurodegenerative diseases, impairs the process of autophagy. This impairs the brain’s ability to clear out toxic proteins. Maraviroc is able to inhibit this switch, helping to restore the self-clearing mechanism of the brain.
How might these findings impact future treatment of neurodegenerative diseases?
These findings hint at potential methods to slow or prevent the build-up of harmful proteins in humans suffering from neurodegenerative diseases. While Maraviroc itself may not be the ultimate solution, it provides a direction for future research and potential drug development. The researchers suggest that other drugs that were not effective against HIV but inhibit CCR5 might effectively prevent neurodegenerative diseases in humans.
Who supported this research?
The research received support from several organizations including Alzheimer’s Research UK, the UK Dementia Research Institute, Alzheimer’s Society, Tau Consortium, Cambridge Centre for Parkinson-Plus, Wellcome, and the European Union’s Horizon 2020 research and innovation program.
More about HIV drug Maraviroc
- University of Cambridge
- UK Dementia Research Institute
- Cambridge Institute for Medical Research
- Alzheimer’s Research UK
- Alzheimer’s Society
- European Union’s Horizon 2020 research and innovation program
- Wellcome
- Tau Consortium
- Cambridge Centre for Parkinson-Plus
- Maraviroc
- Huntington’s disease
- Dementia
- Study: Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration (Link may not lead directly to the article as the future publishing details are part of the fictional context provided by the user.)
4 comments
Wow, this is some pretty amazing stuff! i mean using an HIV drug to slow down dementia? Who’d have thought. Science never fails to amaze!
This is pretty technical, had to read twice to get a grip. But if I get it right, the researchers have found a new way to slow down neurodegenerative diseases? Hats off to them!!
really exciting to see maraviroc being used for something so unexpected. waiting to see if this can be replicated in human trials. Fingers crossed!
Is there any info on when this might be available for humans. know several people who could benefit from something like this…just hoping its sooner rather than later.