Research: New way to spur brain immune cells to clear toxic waste linked to Alzheimer’s disease

By Kimberley Wang, Writer

Researchers have found a “metabolic switch” in the brain’s immune cells that could be targeted as a treatment for Alzheimer’s disease, the most common form of dementia.

The team led by Nanyang Assistant Professor Anna Barron from LKCMedicine discovered that after blocking and turning off this “switch”, brain immune cells called microglia were able to remove toxic proteins that can build up and lead to Alzheimer’s disease.

Microglia tend to be damaged in people with the disease, which makes them less capable of clearing cellular toxic waste. To restore the clean-up function, the scientists “switched off” their inefficient metabolism by preventing a key enzyme from attaching to energy-generating parts of the immune cells.

The findings from lab experiments set the stage for developing drugs that can specifically target metabolism in brain immune cells in order to treat Alzheimer’s disease, which contributes to 60 to 70 per cent of all dementia cases globally. The World Health Organization estimates that 78 million people worldwide will have dementia by 2030.

Such drugs are of high interest in healthcare. While there are ways to treat the symptoms of Alzheimer’s disease, there are currently no definitive cures for the condition, which tends to affect the elderly and impairs people’s ability to think.

Published in Proceedings of the National Academy of Sciences in February 2023, the findings stem from the research team’s work investigating the function of a biomolecule called the translocator protein, which is found in energy-generating parts of immune cells and widely used in clinical research to track inflammation. 

Asst Prof Barron’s group had previously shown that drugs that activated this protein led to less toxic waste build-up in the brain, which improved the condition of mice with Alzheimer’s disease. But how this worked was not clear.

The team cracked the puzzle with their latest experiments on cells from mice with Alzheimer’s. Their work revealed that the translocator protein is critical for the microglia immune cells of the brain to generate their own energy.

Microglia perform the important function of “gobbling up” and removing beta amyloid, a toxic protein whose build-up in the brain causes damage and death to nerve cells, resulting in Alzheimer’s disease. To do their job properly and remove the toxic waste, the immune cells need a lot of energy. 

Without the translocator protein, microglia from mice with Alzheimer’s had an energy problem and could not remove the beta amyloid, which resulted in the disease worsening in the mice. 

Asst Prof Barron explained, “We found that microglia lacking the translocator protein resembled damaged microglia observed in ageing and Alzheimer’s disease. These damaged microglia inefficiently produced energy and could not clean up toxic waste in mice with Alzheimer’s disease.”

The experiments also demonstrated that when the translocator protein is absent, an enzyme called hexokinase-2, which metabolises sugar, kicks into action in microglia to compensate. The enzyme promotes an inefficient way for cells to produce energy. What was surprising was that hexokinase-2 became activated when it stuck to the energy-generating parts of cells called mitochondria.

The researchers found that hexokinase-2 was also activated in microglia when exposed to more toxic forms of beta amyloid, just as it happens in Alzheimer’s disease. They believe this finding helps to partly explain how microglia fail in patients with Alzheimer’s disease and when people age.

To manipulate the enzyme’s role in microglia energy production, they developed a light-activated tool. Their tool involves shining blue light onto a genetically modified version of the hexokinase-2 enzyme to “switch off” one of its functions.

When this happens, it blocks the enzyme’s ability to stick to the energy-generating parts of the microglia and forces the cells to stop relying on an inefficient method of energy production. Experimental results showed that this improves their ability to clear beta amyloid by nearly 20 per cent.

However, if hexokinase-2’s sticking ability is not blocked and its function is disrupted by simply inactivating the enzyme, it does not help the microglia to clear away waste. This insight provides a critical clue for future drug targets.

These findings provide a basis to develop drugs that can act specifically on the metabolism of immune cells in the brain to treat Alzheimer’s disease. For instance, drugs could be developed to prompt the brain’s microglia to produce energy more efficiently and thus clear toxic beta amyloid proteins to protect against Alzheimer’s disease. Such drugs could target the hexokinase-2 enzyme, which is found in the brain’s microglia at high levels in people with Alzheimer’s disease.

The team expects targeted drugs for Alzheimer’s disease to be an improvement over drugs being studied now that do not specifically zero in on metabolism in brain microglia cells. 

The approach of controlling metabolism in microglia using the light-activated tool will also prove useful in studying how energy production works in cells for other diseases and conditions, including diabetes and obesity.

“This tool gives us a way to understand how metabolism contributes to diseases. Historically, this has been hard to study because most approaches to control metabolism are irreversible, lead to toxicity or cannot target cells of interest. However, our tool allows us to control energy processes in specific cells in a reversible way that also doesn’t kill the cells being studied,” said Asst Prof Barron.