The most prevalent form of dementia, Alzheimer’s disease, may one day be treated with medications thanks to a recently identified “energy switch” in the immune cells of the brain. Researchers from Nanyang Technological University in Singapore (NTU Singapore) found that blocking and turning off this “switch” allowed brain immune cells known as microglia to get rid of toxic proteins that can accumulate and cause Alzheimer’s disease.
People with the disease frequently have damaged microglia, which reduces their capacity to remove harmful waste from cells. The researchers “turned off” their poor metabolism by preventing a critical enzyme from adhering to the immune cells’ energy-producing components in order to turn on the clean-up function.
The results of laboratory studies pave the way for the creation of medications that can selectively target immune cells in the brain for the treatment of Alzheimer’s disease, which accounts for 60% to 70% of dementia cases worldwide. By 2030, dementia will be present in 78 million people worldwide, according to the World Health Organization.
Healthcare is quite interested in these medications. While Alzheimer’s disease can have its symptoms treated, there are presently no known therapies for the ailment, which primarily affects the elderly and hinders thinking.
The results of the study, which were released in Proceedings of the National Academy of Sciences in February 2023, are consistent with one of the objectives of the NTU 2025 strategy plan to address the demands and difficulties of healthy aging.
The research, led by Nanyang Assistant Professor Anna Barron from NTU’s Lee Kong Chian School of Medicine, examined the role of a biomolecule known as the translocator protein, which is found in immune cells’ energy-producing regions and is frequently used in clinical studies to monitor inflammation.
It had previously been demonstrated by Asst Prof Barron’s team that medications that activated this protein caused less toxic waste to accumulate in the brain, which improved the health of animals with Alzheimer’s disease. However, it was unclear how this functioned.
In their most recent studies using cells from Alzheimer’s-affected mice, the team was able to solve the puzzle. According to their research, the translocator protein is essential for the brain’s microglia immune cells to produce their own energy.
Beta-amyloid is a harmful peptide that accumulates in the brain and causes damage and death to nerve cells, leading to Alzheimer’s disease. Microglia play a crucial role in “gobbling up” and eliminating beta-amyloid. The immune cells require a lot of energy to function effectively and eliminate poisonous waste.
According to the study, mice with Alzheimer’s disease experienced deteriorating symptoms as a result of their microglia’s energy issues, which prevented them from removing beta-amyloid.
“We found that microglia lacking the translocator protein resembled damaged microglia observed in aging and Alzheimer’s disease,” said Asst Prof Barron. “These damaged microglia inefficiently produced energy and could not clean up toxic waste in mice with Alzheimer’s disease.”
The research also showed that the microglia’s hexokinase-2 enzyme, which metabolizes sugar, activates in the absence of the translocator protein. The enzyme encourages cells to manufacture energy in an ineffective manner. What was unexpected was that hexokinase-2 was activated when it adhered to the mitochondria, which are the components of cells that produce energy.
When microglia were exposed to more hazardous types of beta-amyloid, the researchers discovered that hexokinase-2 was also activated, much as it is in Alzheimer’s disease. According to the researchers, this discovery contributes to the understanding of how microglia malfunction in Alzheimer’s patients and as we age.
The NTU researchers created a light-activated instrument to control the enzyme’s function in the creation of microglia energy. They use the hexokinase-2 enzyme, which has been genetically altered, to “turn off” one of its functions by exposing it to blue light.
When this occurs, it prevents the enzyme from adhering to the microglia’s energy-producing regions, forcing the cells to abandon their reliance on an ineffective mode of energy production. According to experimental findings, this significantly increases their capacity to eliminate beta-amyloid.
However, inactivating hexokinase-2 does not aid in the microglia’s ability to remove waste if the enzyme’s sticking ability is not prevented. This knowledge offers a vital tip for potential pharmacological targets in the future.
According to Asst Prof. Barron, this research gives them a foundation to create medications that target the metabolism of immune cells in the brain to treat Alzheimer’s disease. Drugs may be created, for instance, to encourage the brain’s microglia to make energy more effectively and eliminate harmful beta-amyloid proteins, preventing Alzheimer’s disease.
The hexokinase-2 enzyme, which is abundantly present in the brain microglia of individuals with Alzheimer’s disease, may be the target of such medications.
The research team anticipates that medications for Alzheimer’s disease that precisely target brain microglia metabolism will be superior to those currently being researched.
Senior consultant neurologist Dr. Yeo Tianrong at Singapore’s National Neuroscience Institute, who was not involved in the study, stated that Asst Prof. Barron and her group were able to gain new insights to solve the mystery of energy generation required for microglia to remove beta-amyloid in the brain.
“Importantly, they found that the displacement of hexokinase-2 led to improved energy production and enhanced the microglia’s ability to get rid of beta-amyloid. This is of significance as the strategy of hexokinase-2 displacement represents a potential therapeutic target for improved beta-amyloid removal by the microglia,” said Dr. Yeo.
“The study by Asst Prof Barron’s team highlights the possibility that one day, we can harness the intrinsic capability of microglia to mop up toxic beta-amyloid by re-configuring their energy generating framework,” he added.
The team is preparing tests in mice to see if the findings they made in cells can be duplicated in animals, where physiological factors can have an unanticipated effect on the outcomes.
The method of regulating metabolism in microglia using the light-activated device will also be helpful in research into how cells produce energy for various diseases and ailments, such as 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, leading 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.
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