UC San Diego researchers have actually connected lipid metabolic process modifications to Alzheimers disease progression, identifying potential new treatments by targeting the AMPK enzyme to interrupt a cycle of brain inflammation.Researchers at UC San Diego have actually made use of innovative imaging techniques to explore the metabolic procedures behind Alzheimers disease, resulting in potential brand-new strategies for treatment.Alzheimers illness, the most common type of dementia, substantially impairs memory, believing, and habits, affecting over 50 million people worldwide each year. Forecasts suggest that this number will triple by 2050. Utilizing their own state-of-the-art imaging technologies, researchers at the University of California San Diego have actually now exposed how the metabolic process of lipids, a class of molecule that includes fats, oils, and lots of hormonal agents, is changed in Alzheimers disease. They also revealed a new technique to target this metabolic system with new and existing drugs. The findings are released in Cell Metabolism.”Lipids have been associated with Alzheimers for as long as weve understood about the disease,” stated senior and co-corresponding author Xu Chen, Ph.D., an assistant professor in the Department of Neurosciences at UC San Diego School of Medicine, referring to the initial 1907 report by Alois Alzheimer that explained the uncommon presence of fat deposits in the brain of the very first person to be diagnosed with the disease. “So much of the emphasis ever since has been positioned on tau and other proteins that the research community has, till the last decade approximately, mostly neglected this important element of the disease.”Innovative Imaging Techniques”Driven by a keen interest in lipid droplet functions in aging and illness, we initiated this fruitful cooperation to harness cutting-edge SRS innovation for studying lipid metabolism in tauopathy mouse brains.” Said Yajuan Li, M.D., Ph.D., a postdoctoral researcher in the Shu Chien-Gene Lay Department of Bioengineering at UC San Diego Jacobs School of Engineering. SRS imaging is a technique that examines the method particles in a sample interact with laser light.These images show microglia containing lipid droplets (white areas). Scientists at UC San Diego have exposed that in brains with Alzheimers and associated illness, nerve cells unload excess lipid droplets to microglia, which sets off further swelling. Credit: UC San Diego Health SciencesIn the brain, lipids come in the form of small beads that manage a variety of procedures, such as energy storage and cellular responses to stress. These processes are firmly controlled in typical brains, however in Alzheimers or similar illness, lipid bead metabolic process can malfunction. While researchers comprehend that there is a relationship between Alzheimers and lipid metabolic process, precisely how they influence one another has actually remained a mystery.To answer this question, the group looked directly at lipid droplets in the brains of mice with excess tau protein. They utilized an advanced SRS imaging platform developed in Lingyan Shis lab at the Jacobs School of Engineering. The platform makes it possible to take microscopic images of lipid beads within cells without making use of chemical dyes, which can change the fragile molecules and compromise the implications and results.mechanisms”Intriguingly, the inert lipid beads observed in tauopathy brains display comparable habits to those discovered in aging brains”, stated co-corresponding author Lingyan Shi, Ph.D., assistant teacher of bioengineering at the Jacobs School. “We are now focusing on comprehending the underlying mechanisms by integrating SRS imaging with other using multidisciplinary techniques. Our technique is biologically neutral, so were able to observe whats taking place in the brain at the molecular level with as little disturbance as possible.”Shi and her team, including Li, pioneered the new method, which uses a specially customized variation of water, called heavy water, as a metabolic probe.”Instead of utilizing a typical chemical dye to stain lipids, we use heavy water that is naturally participating in the metabolic activities were interested in,” included Shi. “This gives us a much clearer image of how lipids are formed spatiotemporally, which would not be possible with other techniques. Our existing focus is on understanding the hidden systems of these dynamic changes of lipid metabolism in the context of aging and illness.”The scientists discovered that in brains with tauopathy, nerve cells build up excess lipids as an outcome of stress or damage. This influx forces nerve cells to unload the excess to immune cells in the brain, called microglia. These microglia then mount an inflammatory reaction that triggers additional stress to neurons, triggering a worsening and duplicating cycle.In addition to characterizing this process, they were also able to recognize an important enzyme, called adenosine monophosphate-activated protein kinase (AMPK) that orchestrates the cycle. According to the researchers, breaking this cycle might unlock brand-new treatment choices for Alzheimers illness. Chen is particularly positive about the possibility of repurposing existing drugs that modify lipid metabolism.”We do not think this is an incidental phenomenon,” said Chen. “The evidence suggests that lipid metabolism is a driving system for Alzheimers illness. There are lots of drugs that target lipid metabolism in other body systems, such as in the liver, so we might be able to change this system rather considerably using tools we already have.”Reference: “Microglial lipid bead build-up in tauopathy brain is regulated by neuronal AMPK” by Yajuan Li, Daniel Munoz-Mayorga, Yuhang Nie, Ningxin Kang, Yuren Tao, Jessica Lagerwall, Carla Pernaci, Genevieve Curtin, Nicole G. Coufal, Jerome Mertens, Lingyan Shi and Xu Chen, 23 April 2024, Cell Metabolism.DOI: 10.1016/ j.cmet.2024.03.014 This work was moneyed, in part, by the National Institutes of Health (grants R01AG074273, R01AG078185, 1R01GM149976-01, R01NS111039 R21NS125395) and by the start-up fund from UC San Diego Department of Neurosciences and Jacob School of Engineering.
UC San Diego researchers have linked lipid metabolism changes to Alzheimers illness development, determining prospective new treatments by targeting the AMPK enzyme to interfere with a cycle of brain inflammation.Researchers at UC San Diego have made use of innovative imaging techniques to explore the metabolic processes behind Alzheimers disease, leading to potential new techniques for treatment.Alzheimers illness, the most common type of dementia, considerably impairs memory, believing, and behavior, affecting over 50 million people globally each year.”Lipids have been associated with Alzheimers for as long as weve known about the illness,” said co-corresponding and senior author Xu Chen, Ph.D., an assistant professor in the Department of Neurosciences at UC San Diego School of Medicine, referring to the original 1907 report by Alois Alzheimer that explained the unusual existence of fat deposits in the brain of the first person to be identified with the disease. These procedures are firmly controlled in common brains, but in Alzheimers or similar illness, lipid bead metabolic process can malfunction. While researchers understand that there is a relationship in between Alzheimers and lipid metabolic process, precisely how they influence one another has stayed a mystery.To response this concern, the group looked directly at lipid droplets in the brains of mice with excess tau protein. The platform makes it possible to take microscopic images of lipid droplets within cells without the usage of chemical dyes, which can change the delicate molecules and jeopardize the results.Mechanisms and Implications”Intriguingly, the inert lipid droplets observed in tauopathy brains exhibit comparable behavior to those found in aging brains”, stated co-corresponding author Lingyan Shi, Ph.D., assistant teacher of bioengineering at the Jacobs School.