An HIV drug is showing promise as a treatment for dementia
Author: Greg Owen
Two recent studies have indicated the promise of a well-known HIV drug to treat dementia.
In 2007, the U.S. and European Union approved a drug called Maraviroc (muh-RAV-a-roc) for HIV treatment.
Now, researchers at the University of Cambridge and the University of California at Los Angeles have both shown in independent studies the effectiveness of Maraviroc in treating the conditions that lead to dementia and Huntington’s Disease, another brain-impairing condition, in mice.
In the latest research, from the University of Cambridge, scientists showed how the brain’s ability to clear out toxic proteins is impaired in Huntington’s and other forms of dementia, and how Maraviroc was able to restore this function, helping prevent the toxic build-up and slow the diseases’ progression.
A common characteristic of neurodegenerative disease is the build-up of clusters in the brain called aggregates, including misfolded proteins known as huntingtin and tau. These aggregates lead to the degradation and eventual death of brain cells and the onset of dementia symptoms.
One method mammals use to purge aggregates from the brain is called autophagy (awe-TOFF-o-gee), Latin for “self-eating.” In this process, neighboring cells “eat” the unwanted material, break it down and expel it. Neurodegenerative diseases impair autophagy, leading to a build-up of toxic, misfolded proteins.
In their study, published in the journal Neuron, the team from the Cambridge Institute for Medical Research and the UK Dementia Research Institute at the University of Cambridge identified a process that causes autophagy to fail in mouse models with dementia and Huntington’s, and how Maraviroc helps restore it.
The brain and central nervous system in mammals have specialized immune cells called microglia, dedicated to protecting against unwanted and toxic materials. In neurodegenerative diseases, microglia (mi-KROL-glee-uh) still kick into action, but in a way that actually impairs autophagy, that self-eating process that clears out toxins.
Using mice, the team showed that in the presence of neurodegenerative diseases, those same immunity-boosting microglia release a suite of molecules that activate a switch on the surface of cells called CCR5. That switch perversely impairs autophagy, and the ability of the brain to rid itself of toxic proteins.
Those proteins then aggregate and begin to cause irreversible damage to the brain. Worse still, the same toxins create a feedback loop, leading to a greater response from what should be immunity-boosting microglia, and activating greater numbers of the CCR5 cells, further impairing autophagy and leading to an even faster build-up of the aggregates.
The study’s senior author, Professor David Rubinsztein of the UK Dementia Research Institute at Cambridge, explained in a statement released with the study: “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.”
The team carried out their research using mice that had been genetically altered to develop forms of Huntington’s disease and a type of dementia characterized by the build-up of the tau protein, in particular.
When the researchers used mice bred to “knock out” the action of CCR5 cells, they found that these mice were protected against the build-up of misfolded huntingtin and tau, leading to fewer of the toxic aggregates in the brain when compared to control mice.
Not only is the CCR5 switch exploited by neurodegenerative diseases, it’s also used by HIV as a “doorway” into cells.
That connection inspired the team to use Maraviroc to treat Huntington’s disease mice. Starting at two months old, researchers administered the drug for four weeks. At that point, they found a significant reduction in the number of huntingtin aggregates when compared to untreated mice. But Huntington’s only manifests in mice as mild symptoms by 12 weeks, even without treatment, so it was too early to tell whether Maraviroc would make an impact on the mice’s symptoms.
The same effect was observed in the dementia control group. In these mice, not only did the Maraviroc reduce the amount of tau aggregates compared to untreated mice, it also slowed down brain cell loss. An object recognition test revealed the treated mice performed better than untreated mice, suggesting the drug slowed the loss of memory.
“We’re very excited about these findings because we’ve not just found a new mechanism of how our microglia hasten neurodegeneration,” Rubinsztein said, “we’ve also shown this can be interrupted, potentially even with an existing, safe treatment.”
Halfway around the world, a similar study came to the same conclusion: Maraviroc helps with memory loss in mice.
In May last year, UCLA neuroscientist Alcino Silva was also studying the effect of the CCR5 switch on memory, specifically how memory connections are made. As the brain gets older, it can still form new memories, but it has trouble linking them together, Silva told NPR.
“You learn about something,” Silva explained, “but you can’t remember where you heard it. You can’t remember who told you about it. These incidents happen more and more often as we go from middle age into older age.”
It turns out that just as CCR5 affects the build-up of toxic proteins in the brain, it interferes with the process of memory linkage, like putting together a name and a face.
“Then you no longer link memories after that because that molecule turns off memory mechanisms,” said Silva.
Then Silva’s team, like the Cambridge study group, tried Maraviroc. Just as it restored autophagy function, clearing out toxic proteins, Maraviroc helped restore memory linking.
Silva, whose research was published in Nature, discovered in a previous study with Thomas Carmichael, the chair of neurology at UCLA, that levels of CCR5 rise sharply after a stroke. Now Carmichael is applying Silva’s research with Maraviroc to stroke patients.
“You might have an effect in Alzheimer’s disease and stroke and Parkinson’s and also in spinal cord injury,” Carmichael said.
“Maraviroc may not itself turn out to be the magic bullet, but it shows a possible way forward,” said Rubinsztein of the Cambridge study. “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.”
Actual Story on LGBTQ Nation
Author: Greg Owen