Scientists from the Cambridge Institute for Medical Research and the UK Dementia Research Institute at the University of Cambridge say they have demonstrated in a mouse study that an HIV drug was able to restore the function of the brain’s ability to clear out toxic proteins impaired in Huntington’s disease and other forms of dementia.
The findings are published in Neuron in an article titled, “Microglial-to-neuronal CCR5 signaling regulates autophagy in neurodegeneration.”
“In neurodegenerative diseases, microglia switch to an activated state, which results in excessive secretion of pro-inflammatory factors,” wrote the researchers. “Our work aims to investigate how this paracrine signaling affects neuronal function. Here, we show that activated microglia mediate non-cell-autonomous inhibition of neuronal autophagy, a degradative pathway critical for the removal of toxic, aggregate-prone proteins accumulating in neurodegenerative diseases. We found that the microglial-derived CCL-3/-4/-5 bind and activate neuronal CCR5, which in turn promotes mTORC1 activation and disrupts autophagy and aggregate-prone protein clearance.”
The team carried out their research using mice that had been genetically altered to develop forms of Huntington’s disease or a type of dementia characterized by the build-up of the tau protein.
The team showed that in neurodegenerative diseases, microglia release a suite of molecules that activate a switch on the surface of cells. When activated, the switch, called CCR5, impairs autophagy, and the brain’s ability to rid itself of the toxic proteins.
“The microglia begin releasing these chemicals long before any physical signs of the disease are apparent,” said David Rubinsztein, PhD, a professor from the UK Dementia Research Institute at the University of Cambridge, the study’s senior author. “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 action of CCR5, they found that these mice were protected against the build-up of misfolded huntingtin and tau.
The team then used maraviroc, a prescription medicine approved by the FDA for the treatment of HIV infection in adults and children, to treat the Huntington’s disease mice. The drug was administered for four weeks when the mice were two months old. When the researchers observed the mice’s brains, they found a significant reduction in the number of huntingtin aggregates when compared to untreated mice. However, it was too early to see whether the drug would make an impact on the mice’s symptoms.
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 an 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.”