How Neurodegenerative Diseases Disrupt Brain Fat Processing

ROCKVILLE, MD – Tau protein tangles are a hallmark of Alzheimer’s, but new research reveals that tau has a critical role in regulating fat metabolism in the brain; when tau become dysfunctional it may promote the buildup of toxic fats, contributing to disrupted fat metabolism and neurodegeneration.

“Historically, neurodegeneration has been studied from the protein side. But in recent years, there is more research coming out that is correlating the disease with changes in the lipids, or fats, in the brain,” said Anna Oliveras, PhD, a postdoctoral researcher in the lab of Melissa Birol at the Berlin Institute for Medical Systems Biology in Germany.

Oliveras and colleagues’ latest research suggests that tau doesn’t just form tangles; it also forms dynamic, droplet-like structures within cells as it spreads from one cell to another. And this spreading, the research found, has a significant impact on how the brain handles fats. The work will be presented at the 69th Biophysical Society Annual Meeting, to be held February 15 – 19, 2025 in Los Angeles.

Oliveras used advanced imaging and molecular techniques to study how tau spreads and interacts with lipids within human cell derived, brain-like models grown in the lab. “Tau actually regulates lipid metabolism and helps to transport lipids, especially peroxidated lipids, which are the lipids that are oxidized and are harmful for the neurons,” Oliveras explained.

The team found that tau behaves differently in different types of brain cells. In neurons, the cells that transmit information, tau forms these dynamic droplets with fats. Interestingly, the tau in neurons seems to promote the transfer of fatty acids to the astrocytes, support cells in the brain, which further remove these lipids to avoid lipid toxicity.

Even more surprising, the researchers discovered that tau helps clear out damaged, peroxidized lipids from neurons. This suggests that the tau-fat assemblies are actually a way for the brain to protect itself from toxic lipid buildup.

However, tau’s interaction with lipids seems to be a double-edged sword. While it might initially be trying to protect the brain, the progressive accumulation and spread of tau likely overwhelms this protective mechanism, ultimately leading to the lipid imbalances we see in these diseases.

This discovery is crucial because it links the early stages of tau spread to disruptions in brain fat metabolism, a connection that has long been suspected but not well understood. By targeting these tau-lipid interactions, scientists may be able to develop new therapies to prevent or slow the progression of tauopathies like Alzheimer’s disease.

“We are trying to understand the physiological function of tau and its relationship with lipids. This could help in the future to find markers that can indicate if someone has the disease before they develop symptoms. It can also help us to look for treatments,” Oliveras said.

Image Caption:

Live imaging of a brain organoid, with tau shown in red, lipids in white and cell nuclei in blue. Image courtesy of Anna Oliveras.

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