Research shows HIV drug could help clear toxic proteins linked to dementia and Huntington's disease

While the researchers acknowledged that it's premature to conclude that the drug can prevent dementia or Huntington's disease in humans, they emphasized that it has identified a biological pathway that leads to neurodegeneration and could potentially offer a means to impede it.

Restoring autophagy to clear toxic proteins

As said in the release, neurodegenerative conditions like Huntington's disease and dementia are characterized by the accumulation of harmful proteins in the brain due to the breakdown of the body's natural autophagy process.

Researchers have found that microglia, immune cells in the brain, become activated and release molecules that activate the CCR5 receptor located on neurons' outer surface. When CCR5 is activated, it interferes with autophagy, causing the accumulation of toxic protein clusters. This leads to a feedback loop, resulting in the activation of even more CCR5 receptors.

In order to investigate methods of inhibiting this cycle, the scientists developed a unique strain of mice that were genetically engineered to lack CCR5, which resulted in a reduced accumulation of misshapen proteins in their brains when compared to the control group of mice.

Potential new pathways for treating neurodegeneration

The research offers a fresh understanding of the underlying causes of neurodegeneration and presents a potential strategy to combat it. In addition, recent findings suggest that a widely used sleeping medication could alleviate the accumulation of comparable toxic proteins linked to Alzheimer's disease in humans. The existence of two potential avenues for scientists to explore in the quest for preventing neurodegenerative diseases is encouraging.

While maraviroc may not itself turn out to be the magic bullet, it shows a possible way forward, according to neuroscientist David Rubinsztein, who led the research. Rubinsztein also said, "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." 

The study suggests the potential for developing effective treatments for neurodegenerative diseases, but it emphasizes the importance of initiating treatment before symptoms appear.

Study Abstract

In neurodegenerative diseases, microglia switch to an activated state, which results in excessive secretion of pro-inflammatory factors. 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 activates neuronal CCR5, which in turn promotes mTORC1 activation and disrupts autophagy and aggregate-prone protein clearance. CCR5 and its cognate chemokines are upregulated in the brains of pre-manifesting mouse models for Huntington’s disease (HD) and tauopathy, suggesting a pathological role of this microglia-neuronal axis in the early phases of these diseases. CCR5 upregulation is self-sustaining, as CCL5-CCR5 autophagy inhibition impairs CCR5 degradation itself. Finally, pharmacological or genetic inhibition of CCR5 rescues mTORC1 hyperactivation and autophagy dysfunction, which ameliorates HD and tau pathologies in mouse models.