Maraviroc — a drug used to treat human immunodeficiency virus (HIV) — shows potential to be repurposed to slow down, or even prevent, the development of dementia. This is the conclusion of a from the University of Cambridge, which found that the drug stops the brain’s immune cells from accidentally interfering with a key cellular recycling process. This, in turn, prevents the harmful buildup of proteins within the brain that causes cellular degradation and death — and the resultant onset of dementia symptoms.
Autophagy — literally “self-devouring” — is a recycling method employed by the body in which cells rid themselves of junk parts and toxic materials by recycling what can be salvaged and disposing of the rest.
In neurodegenerative diseases like Huntington’s and various forms of dementia, however, this process does not work correctly.
In the brain of individuals with these diseases, misfolded versions of proteins like huntingtin (which is involved in transport within nerve fibres) and tau (which stabilise the structure of the fibres) build up in clusters known as “aggregates”.
The presence of these aggregates leads to the degradation and eventually death of brain cells — and the onset of noticeable symptoms.
In the new study, the researchers identified a process that disrupts autophagy in mouse models of both Huntington’s disease and a form of dementia.
(For the latter, the mice had been genetically engineered to develop versions of these diseases that are characterised by the build-up of the tau protein.)
Moreover, the team has also found a drug that can help restore this vital cellular function.
Their findings are centred around a specialist form of immune cell — unique to the brain and the central nervous system — called “microglia”. Ordinarily, these cells act to protect the body against unwanted and toxic materials.
In people with neurodegenerative diseases, however, when the microglia kick into action, they release a suite of molecules which activate a switch, known as “CCR5”, on the surface of cells, that unhelpfully interferes with the process of autophagy.
Not only does this lead to a buildup of toxic proteins that cause irreversible damage to the brain, but these proteins also trigger more CCR5 activity — forging a feedback loop that causes the harmful aggregates to build up even faster still.
Paper author and Cambridge molecular neurogeneticist Professor David Rubinsztein 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 studied mice that were further edited such that their CCR5 switch was non-functional, they found that these animals were protected against the build-up of misfolded huntingtin and tau proteins.
As a result, they developed lower levels of toxic aggregates in their brain than the mice in which CCR5 had not been “knocked out”.
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Understanding the role of CCR5 provided the team with a clue as to how the development of certain neurodegenerative diseases in humans might be slowed down or even prevented.
The switch not only facilitates neurodegenerative diseases, however — it is also used by HIV as a “doorway” into cells.
In fact, in 2007 both the United States and the European Union approved the use of a CCR5-inhibiting drug known as “maraviroc” for the treatment of HIV.
After the researchers gave a four-week course of maraviroc to the Huntington’s disease mice, starting at two months of age, they found a significant reduction in the number of huntingtin aggregates in comparison with untreated control mice.
(The team did caution, however, that as Huntington’s only manifests mild symptoms in mice after 12 weeks without treatment, their study was unable to reveal whether or not the maraviroc had an impact on the mice’s symptoms.)
A similar effect was also seen in the dementia mice. In these rodents, not only did the drug reduce the levels of tau aggregates in comparison with untreated cells, but it was also seen to slow down the loss of brain cells.
The treated mice also performed better than untreated mice in an object recognition test, suggesting that the drug was also successful in slowing down memory loss.
Prof. 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.”
The full findings of the study were published in the journal Neuron.
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