They are part of the NTU group that found a “metabolic switch” in brain immune cells that could be targeted as a possible treatment for Alzheimers disease. The experiments likewise demonstrated that when the translocator protein is absent, an enzyme called hexokinase-2, which metabolizes sugar, kicks into action in microglia to compensate. The enzyme promotes an ineffective method for cells to produce energy. Historically, this has actually been hard to study due to the fact that many approaches to manage metabolic process are permanent, lead to toxicity, or can not target cells of interest. Our tool permits us to control energy processes in particular cells in a reversible method that also does not eliminate the cells being studied,” said Asst Prof Barron.
The findings from laboratory experiments set the stage for developing drugs that can specifically target metabolic process in brain immune cells in order to treat Alzheimers illness, which contributes to 60 to 70 percent of all dementia cases globally. The World Health Organisation estimates that 78 million people worldwide will have dementia by 2030.
From left: Research fellow Dr Wong Jia Hui, Nanyang Asst Prof Anna Barron, and final year PhD trainee Ms Lai Kei Onn from Nanyang Technological University, Singapores Lee Kong Chian School of Medicine. They become part of the NTU group that discovered a “metabolic switch” in brain immune cells that could be targeted as a possible treatment for Alzheimers disease. Credit: NTU Singapore
Such drugs are of high interest in healthcare. While there are ways to deal with the signs of Alzheimers illness, there are presently no conclusive treatments for the condition, which tends to impact the elderly and impairs individualss ability to believe.
The researchers findings, which were published in Proceedings of the National Academy of Sciences in February 2023, are in line with one of the goals of the NTU 2025 tactical strategy to react to the needs and challenges of healthy living and aging.
Cracking a metabolic process puzzle
The findings of the researchers, led by Nanyang Assistant Professor Anna Barron from NTUs Lee Kong Chian School of Medicine, come from their work examining the function of a biomolecule called the translocator protein, which is discovered in energy-generating parts of immune cells and which is extensively used in medical research to track inflammation.
Asst Prof Barrons group had formerly shown that drugs that triggered this protein resulted in less harmful waste accumulation in the brain, which improved the condition of mice with Alzheimers disease. However how this worked was not clear.
The group split the puzzle with their latest experiments on cells from mice with Alzheimers. Their work exposed 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 triggers damage and death to nerve cells, leading to Alzheimers illness. To do their job properly and remove the poisonous waste, the immune cells require a lot of energy.
The research group showed that without the translocator protein, microglia from mice with Alzheimers had an energy problem and could not eliminate the beta-amyloid, which resulted in the illness getting worse in the mice.
” We found that microglia doing not have the translocator protein resembled damaged microglia observed in aging and Alzheimers disease,” said Asst Prof Barron. “These damaged microglia inefficiently produced energy and might not clean up toxic waste in mice with Alzheimers disease.”
The experiments also showed that when the translocator protein is absent, an enzyme called hexokinase-2, which metabolizes sugar, kicks into action in microglia to compensate. The enzyme promotes an ineffective method for cells to produce energy. What was surprising was that hexokinase-2 ended up being triggered when it stuck to the energy-generating parts of cells called mitochondria.
The scientists found that hexokinase-2 was also triggered in microglia when exposed to more harmful forms of beta-amyloid, simply as takes place in Alzheimers illness. When individuals age, the researchers believe this finding assists to partly describe how microglia fail in patients with Alzheimers disease and.
To control the enzymes role in microglia energy production, the NTU researchers established a light-activated tool. Their tool includes shining blue light onto a genetically customized variation of the hexokinase-2 enzyme to “turn off” one of its functions.
When this occurs, it obstructs the enzymes capability to stick to the energy-generating parts of the microglia and requires the cells to stop depending on an ineffective approach of energy production. Experimental outcomes revealed that this enhances their ability to clear beta-amyloid by nearly 20 percent.
However, if hexokinase-2s sticking ability is not blocked and its function is interfered with by merely inactivating the enzyme, it does not assist the microglia to eliminate waste. This insight supplies an important hint for future drug targets.
Targeted drug advancement
Asst Prof Barron stated that her groups findings supply a basis for them to develop drugs that can act specifically on the metabolism of immune cells in the brain to treat Alzheimers disease.
Drugs could be established to trigger the brains microglia to produce energy more effectively and therefore clear toxic beta-amyloid proteins to protect against Alzheimers illness.
Such drugs could target the hexokinase-2 enzyme, which is found in the brains microglia at high levels in people with Alzheimers illness.
The group anticipates targeted drugs for Alzheimers illness to be an improvement over those drugs being studied now that do not particularly zero in on metabolism in brain microglia cells.
Dr. Yeo Tianrong, a senior specialist neurologist at Singapores National Neuroscience Institute who was not associated with the research study, said that Asst Prof Barron and her team had the ability to gain brand-new insights to piece together the puzzle of energy generation that is required for microglia to get rid of beta-amyloid in the brain.
” Importantly, they discovered that the displacement of hexokinase-2 resulted in improved energy production and enhanced the microglias capability to eliminate beta-amyloid. This is of significance as the technique of hexokinase-2 displacement represents a potential therapeutic target for enhanced beta-amyloid elimination by the microglia,” said Dr. Yeo.
” The research study by Asst Prof Barrons group highlights the possibility that, one day, we can harness the intrinsic ability of microglia to mop up poisonous beta-amyloid by re-configuring their energy creating framework,” he included.
Future research study that the group is preparing includes experiments in mice to verify that what they observed in cells can be duplicated in animals, where physiological conditions might have an unforeseen effect on the results.
The approach of managing metabolism in microglia utilizing the light-activated tool will likewise show beneficial in studying how energy production operates in cells for other illness and conditions, including diabetes and obesity.
” This tool provides us a method to understand how metabolic process adds to illness. Historically, this has been tough to study because most methods to manage metabolism are permanent, cause toxicity, or can not target cells of interest. However, our tool allows us to manage energy procedures in particular cells in a reversible manner in which likewise doesnt kill the cells being studied,” stated Asst Prof Barron.
Referral: “Mitochondrial control of microglial phagocytosis by the translocator protein and hexokinase 2 in Alzheimers disease” by Lauren H. Fairley, Kei Onn Lai, Jia Hui Wong, Wei Jing Chong, Anselm Salvatore Vincent, Giuseppe DAgostino, Xiaoting Wu, Roshan R. Naik, Anusha Jayaraman, Sarah R. Langley, Christiane Ruedl and Anna M. Barron, 14 February 2023, Proceedings of the National Academy of Sciences.DOI: 10.1073/ pnas.2209177120.
The study was funded by the Ministry of Education– Singapore and Nanyang Technological University.
A picture of brain immune cells called microglia (green) clustering around an accumulation of poisonous beta-amyloid (red). Credit: LKCMedicine/NTU Singapore
Researchers have discovered a “metabolic switch” in the brains immune cells that could work as a target for Alzheimers illness treatment.
A recent discovery of an “energy switch” within immune cells in the brain holds guarantee for the production of drugs to treat Alzheimers illness, which is the most extensive type of dementia.
Researchers at Nanyang Technological University in Singapore have actually uncovered that by obstructing and deactivating the previously mentioned “switch”, microglial immune cells in the brain had the ability to get rid of hazardous proteins that can construct up and result in Alzheimers illness.
Microglia tend to be harmed in people with the illness, which makes them less efficient in clearing cellular toxic waste. To restore the clean-up function, the scientists “turned off” their ineffective metabolic process by preventing an essential enzyme from attaching to energy-generating parts of the immune cells.