How Alzheimer’s and Fat Metabolism are Linked

Alzheimer’s disease causes significant memory, thinking and behavioral problems, and is the most common form of dementia, affecting more than 50 million people worldwide each year. This number is expected to triple by 2050. Using their own cutting-edge imaging technologies, scientists at the University of California San Diego, led by Xu Chen, Ph.D., assistant professor in the Department of Neuroscience at UC, have now uncovered how the metabolism of lipids, a class of molecules that includes fats, oils and many hormones, is altered in Alzheimer’s disease. They have also revealed a new strategy to target this metabolic system with new and existing drugs. The findings were published in the journal Cell Metabolism.

Link Between Alzheimer’s and Lipid Metabolism

According to Xu Chen, lipids have long been associated with Alzheimer’s disease. The expert refers to the original report by Alois Alzheimer in 1907, which described the unusual presence of fat deposits in the brain of the first person diagnosed with the disease. Since then, so much focus has been placed on tau and other proteins that the research community largely overlooked this important aspect of the disease until about ten years ago.

Driven by their keen interest in the functions of lipid droplets in aging and disease, the researchers initiated this fruitful collaboration to utilize cutting-edge SRS technology to study lipid metabolism in tauopathy mouse brains. SRS imaging analyzes the way molecules in a sample interact with laser light. In the brain, lipids come in the form of tiny droplets that control a variety of processes, such as energy storage and how cells respond to stress. These processes are tightly regulated in normal brains, but in Alzheimer’s or similar diseases, the metabolism of lipid droplets can be disturbed. Scientists know that there is a link between Alzheimer’s and lipid metabolism, but exactly how they influence each other has remained a mystery.

To answer this question, the team directly examined lipid droplets in the brains of mice with excess tau protein. They used a state-of-the-art SRS imaging platform developed in the lab at the Jacobs School of Engineering. The platform makes it possible to capture microscopic images of lipid droplets in cells without using chemical dyes, which can alter the sensitive molecules and interfere with the results.

Interestingly, the inert lipid droplets observed in tauopathy brains show similar behavior to those observed in aging brains. The researchers are now focusing on understanding the underlying mechanisms by combining SRS imaging with other multidisciplinary techniques. Their approach is biologically neutral, so they are able to observe what is happening in the brain at the molecular level with as little interference as possible.

Instead of using a typical chemical dye to stain lipids, the researchers use heavy water, which is naturally involved in the metabolic activities they are interested in. This gives them a much clearer picture of how lipids are formed spatially and temporally, which would not be possible with other approaches. They are currently focusing on understanding the underlying mechanisms of these dynamic changes in lipid metabolism in the context of ageing and disease.

New Treatment Options for Alzheimer’s Disease

The researchers discovered that in brains with tauopathy, neurons accumulate excess lipids as a result of stress or damage. This influx forces the neurons to offload the excess onto immune cells in the brain, known as microglia. These microglia then trigger an inflammatory response that further stresses the neurons, triggering a repetitive and worsening cycle.

In addition to characterizing this process, they were also able to identify a crucial enzyme called adenosine monophosphate-activated protein kinase (AMPK) that controls the cycle. According to the researchers, interrupting this cycle could open up new treatment options for Alzheimer’s disease. Chen is particularly optimistic about the possibility of repurposing existing drugs that alter lipid metabolism. According to the experts, the evidence suggests that lipid metabolism is a driving mechanism for Alzheimer’s disease. There are many drugs that target lipid metabolism in other body systems, such as the liver, so they may be able to dramatically alter this system with the drugs that are already available.