Exploring a Novel Treatment to Halt Neuronal Autophagy and Reduce Neurodegenerative Disease

Sunday - April 30 2023, 18:41 UTC - 1 year ago

Researchers at the University of Cambridge have uncovered the potential of an HIV drug, maraviroc, to clear toxic proteins associated with Huntington's disease, a specific form of dementia, and other neurodegenerative conditions. The study showed that, when the drug was administered to mice with dementia, they were able to restore the brain's capacity to eliminate toxic proteins. This, in turn, caused a reduction in brain cell death and a deceleration in memory loss. The findings suggest that the drug could potentially be a means to impede the development of neurodegenerative diseases.

The potential of an HIV drug, maraviroc, in clearing toxic proteins linked to neurodegeneration has been uncovered by researchers at the University of Cambridge. The drug has shown promise in clearing out toxic proteins associated with Huntington's disease and a specific form of dementia.

According to the study, mice genetically engineered to have dementia showed a restoration in the brain's capacity to eliminate toxic protein clusters when treated with maraviroc. This resulted in a reduction in brain cell death and a deceleration in memory loss. The study suggests that the use of the HIV drug as a therapy for neurodegenerative disorders is a possibility.

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 necessary for neuronal survival. We identified that the chemokine receptor CCR5, previously shown to act as a functional receptor to HIV-1 gp120, is upregulated on the neuronal surface and CCR5 agonists are secreted by activated microglia and cause neuronal autophagy inhibition. We also find that the administration of a FDA-approved CCR5 antagonist, maraviroc, is able to rescue autophagy in neurons and prevent neuronal demise in a mouse model of Huntington’s disease. Our findings identify a new mechanism of neuronal demise in neurodegenerative diseases and a new potential therapeutic target with repurposed drugs.