Fighting Alzheimer's with 'decoy receptors'

One day, it might be possible to harness the immune system and coerce it into tackling Alzheimer's disease. A recent study brings us one step closer to making this a reality.

Alzheimer's disease is a neurodegenerative condition that affects around 5.7 million individuals in the United States.

Around 1 in 10 people over the age of 65 have Alzheimer's. Despite its worrying prevalence, there is still no cure and no way to slow its progression.

The exact mechanisms behind Alzheimer's are not fully understood, but a toxic buildup of a protein called beta-amyloid is known to be important. As levels of amyloid plaques increase, nerve cells begin to die off.

Over the years, it has become increasingly clear that the immune system plays a role in this disruptive condition. However, it is a complicated and double-edged relationship.

For instance, the immune system has the potential to slow Alzheimer's progression by clearing up toxic protein; on the other hand, immune cells can react to amyloid plaques and trigger an inflammatory response that, in the long run, causes more damage to brain tissue.

The importance of microglia

One type of immune cell that seems pivotal is microglia, which are a type of macrophage that forms the brain's first line of defense. These cells are responsible for clearing the brain of debris, toxins, and pathogens.

In Alzheimer's disease, however, microglia do not fulfill their duty. Dysfunction of these cells may, at least in part, be responsible for the buildup of amyloid plaques in the brain.

The latest research into Alzheimer's and the immune response comes from the University of Florida in Gainesville. Led by Paramita Chakrabarty, Ph.D., and Dr. Todd E. Golde, the scientists were particularly interested in a family of proteins called toll-like receptors (TLRs).

TLRs sit on the surface of immune cells; they detect molecules that come from broken cells or invading pathogens and trigger an immune attack.

The researchers found that, in the brains of individuals with Alzheimer's disease, there were significantly more TLRs. This was predominantly due to an increased number of microglia.

The researchers hypothesized that if they separated some of the TLRs from the surface of microglia, they might act as "decoy receptors," reducing the buildup of amyloid plaques.

Aggregation of proteins would be avoided because the free-floating TLRs would soak up the beta-amyloid before it got chance to clump together. This might also prevent the errant proteins from binding to microglia and triggering damaging inflammation.

As the team predicted, applying this approach to one subtype of TLR called TLR5 did prevent, and perhaps even reverse, amyloid plaque formation in an Alzheimer's mouse model.

Paradigm shift in Alzheimer's research

As the study authors write, this approach marks a "paradigm shift" in the study of Alzheimer's and the immune system; rather than introducing "highly engineered" antibodies to target amyloid plaques, they employ a decoy approach using a protein that is naturally present.

The authors hope this could eventually lead to a relatively safe way of treating Alzheimer's disease. Their findings were recently published in the Journal of Experimental Medicine.

The results are exciting, but Chakrabarty recommends caution, saying, "This mouse model is well recognized as a primary model for Alzheimer-type amyloid plaque deposition, but it does not recapitulate the entire Alzheimer's neurodegenerative cascade."

"Therefore, the potential of soluble TLR5 in dampening immune activation and related neurotoxic pathways need to be further explored in multiple models of Alzheimer's disease."

"By directly interacting with beta-amyloid and attenuating beta-amyloid levels in mice, the soluble TLR5 decoy receptor represents a novel and potentially safe class of immunomodulatory agents for Alzheimer's disease."

Dr. Todd E. Golde

Using this technique to treat humans is still a long way down the road, but the new findings provide hope. Because the burden of Alzheimer's on the U.S. population is so substantial, research into the disease is running at breakneck speed.

No doubt this new course of action will be swiftly expanded upon.