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25 Apr 2024
Raman-based platform shows details of lipid build up, suggests future treatment strategies.
A project at the University of California, San Diego has used a Raman-based imaging platform to explore the metabolism behind Alzheimer's disease.
Published in Cell Metabolism, the results indicate a potential new strategy to treat the disease, and so tackle a major global health challenge.
In particular, the project sought a way to image particular lipid accumulations known to be associated with development of the disease but not closely studied before now. To date researchers have concentrated instead on studying proteins called tau proteins, and examine how they become tangled with neurons.
Lipids in the form of tiny droplets control a variety of processes in the brain, normally tightly regulated. In Alzheimer’s or similar diseases, lipid droplet metabolism can malfunction, although exactly how and in what circumstances this influences the progress of the disease has not been specifically investigated.
"Lipids have been associated with Alzheimer's for as long as we've known about the disease,” said Xu Chen from UC San Diego School of Medicine.
"So much of the emphasis since then has been placed on tau and other proteins that the research community has, until the last decade or so, largely overlooked this important aspect of the disease."
The new imaging platform is based on stimulated Raman scattering (SRS) microscopy combined with the use of deuterium oxide - heavy water - as a metabolic probe. This represents a development of previous studies of metabolic dynamics in living cells using a similar approach.
In 2018 a project at Columbia University developed deuterium oxide probing and stimulated Raman scattering (DO-SRS) as a potential method of tracking tumor boundaries and malignancies in tissues, testing its approach on mice. That project team included Lingyan Shi, now head of UC San Diego's Laboratory of Optical Bioimaging and Spectroscopy and co-author of the new study.
Breaking the lipid cycle to treat Alzheimer's
"Instead of using a typical chemical dye to stain lipids, we use heavy water that is naturally participating in the metabolic activities we’re interested in," commented Shi.
"This gives us a much clearer picture of how lipids are formed spatiotemporally, which would not be possible with other approaches. Our current focus is on comprehending the underlying mechanisms of these dynamic changes of lipid metabolism in the context of aging and diseases."
Using DO-SRS makes it possible to image lipid droplets within cells without the use chemical dyes, which can alter the delicate molecules and compromise the results. This in turn allowed the team to visualize lipid droplet accumulation in mouse and fly test subjects, and characterize the role of particular protein pathways in regulating how lipid droplets behave.
This led to the discovery that one enzyme, adenosine monophosphate-activated protein kinase (AMPK), orchestrates the cycle of lipid droplet accumulation. Breaking this cycle could unlock new treatment options for Alzheimer’s disease, including the possibility of repurposing existing drugs that modify lipid metabolism.
"The evidence suggests that lipid metabolism is a driving mechanism for Alzheimer’s disease," said Xu Chen. "There are many drugs that target lipid metabolism in other body systems, such as in the liver, so we might be able to change this system quite dramatically using tools we already have."
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