A repurposed HIV drug can restore the brain’s ability to clear out toxic proteins, helping to prevent the dangerous build-up seen in Huntington’s disease and other neurological diseases, researchers reported last night.
In a mouse model, researchers from the University of Cambridge, UK, identified a process that causes autophagy not to work properly in the brains of mouse models of Huntington’s disease and a form of dementia.
In neurodegenerative diseases such as Huntington’s disease there is a build up of aggregates of misfolded proteins, such as huntingtin and tau, which lead to the degradation and eventual death of brain cells and the onset of symptoms.
Bodies usually rid themselves of toxic materials by the process of autophagy, but because this does not work properly in neurodegenerative diseases, the misfolded proteins are unable to leave the body.
The study, published in the latest edition of Neuron, a team from the Cambridge Institute for Medical Research and the UK Dementia Research Institute at the University of Cambridge involved using mice that had been genetically altered to develop forms of Huntington’s disease or a type of dementia characterised by the build-up of the tau protein.
The brain and central nervous system have microglia, which should protect against unwanted and toxic materials but in neurodegenerative diseases, it impairs the process of autophagy.
The team found that in neurodegenerative diseases, microglia release a suite of molecules which in turn activate CCR5, a switch on the surface of cells. When activated, CCR5 impairs autophagy and the proteins aggregate and begin to cause irreversible damage to the brain.
Senior study author Professor David Rubinsztein from the UK Dementia Research Institute at the University of Cambridge said: “The microglia begin releasing these chemicals long before any physical signs of the disease are apparent. This suggests – much as we expected – that if we’re going to find effective treatments for diseases such as Huntington’s and dementia, these treatments will need to begin before an individual begins showing symptoms.”
When the researchers used mice bred to “knock out” the CCR5 action, those mice were protected against the build-up of misfolded huntingtin and tau, which resulted in fewer of the toxic aggregates in the brain when compared to control mice.
The researchers say this finding is revealing clues to how this build-up could in future be slowed or prevented in humans.
Because the CCR5 switch is also used by HIV as a “doorway” into our cells and the approved HIV drug maraviroc inhibits CCR5, the team went on to use maraviroc to treat the mice with Huntington’s disease.
They administered the drug for four weeks when the mice were two months old and found a significant reduction in the number of huntingtin aggregates compared to untreated mice.
However, as Huntington’s disease only manifests in mice as mild symptoms by 12 weeks even without treatment, it was too early to see whether the drug would make an impact on the mice’s symptoms.
The same effect was observed in the dementia mice, where the drug reduced the amount of tau aggregates compared to untreated mice and slowed down the loss of brain cells.
Professor Rubinsztein added: “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 may not itself turn out to be the magic bullet, but it shows a possible way forward. During the development of this drug as a HIV treatment, there were a number of other candidates that failed along the way because they were not effective against HIV. We may find that one of these works effectively in humans to prevent neurodegenerative diseases.”
Festa BP, Siddiqi FH, Jimenez-Sanchez M et al. Microglial-to-neuronal CCR5 signalling regulates autophagy in neurodegeneration. Neuron. 26 April 2023; doi: 10.1016/j.neuron.2023.04.006
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