Researchers Discover Neuroprotective Function of Tau Protein

A study led by researchers at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital reveals that tau, a key player in several neurodegenerative diseases including Alzheimer’s, also plays a positive role in the brain. Tau mitigates neuronal damage caused by excess reactive oxygen species (ROS) or free radicals and promotes healthy aging. The study was published in Neuroscience of Nature.

“ROS are natural byproducts of various cellular functions in the body. While low levels of ROS are beneficial, excess ROS is harmful to cells because it triggers the production of toxic forms of other molecules that induce oxidative stress, including peroxidized lipids,” said lead author Dr. Lindsey Goodman, a postdoctoral researcher in Dr. Hugo Bellen’s lab.

“Neurons are particularly sensitive to oxidative stress and are destroyed if peroxidized lipid levels are not tightly controlled.”

Lipid droplets protect the brain from oxidative damage

Growing evidence supports the idea that our brain has evolved multiple neuroprotective strategies to combat ROS-induced oxidative damage.

One strategy Bellen’s team discovered in 2015 is for neurons to export these toxic peroxidized lipids to nearby glial cells, which sequester them in lipid droplets for storage and energy production. “This process effectively removes and neutralizes these toxic lipids,” Goodman said. “In the current study, we investigated the role of tau in the formation of glial lipid droplets.”

The team found that normal endogenous tau protein in flies is required for glial lipid droplet formation and protection against neuronal ROS. Similarly, tau protein was required in glial cells obtained from rats and humans to form lipid droplets.

And while expression of normal human tau was sufficient to restore the process of glial lipid droplet formation and maturation in flies lacking their own tau, when human tau carried disease-causing mutations—which are linked to an increased risk of Alzheimer’s disease—the glia were unable to form lipid droplets in response to neuronal ROS.

“These results suggest that tau mutations may reduce the protein’s normal ability to prevent oxidative stress in addition to causing accumulation of the protein in typical disease-related features, as described in previous work,” Goodman said. “Overall, the results support a novel neuroprotective role for tau against ROS-associated toxicity.”

Too much or too little Tau is harmful

Further links to disease were discovered using established fly and rat models of Tau-mediated conditions that overexpress the disease-causing human Tau protein in glia. In these scenarios, the researchers again observed defects in glial lipid droplets and glial cell death in response to neuronal ROS. This demonstrated that Tau is a dosage-sensitive regulator of glial lipid droplets where too much or too little Tau is detrimental.

“By revealing a surprising new neuroprotective role for Tau, the study opens the door to potential new strategies to slow, reverse and treat neurodegenerative diseases,” said Bellen, the study’s corresponding author. He is a professor emeritus of molecular biology and genetics at Baylor and holds an endowed chair in neurogenetics at Duncan NRI. Bellen is also the March of Dimes Professor of Developmental Biology at Baylor.

In summary, unlike its usual role as a “bad guy” in neurodegenerative diseases, this study demonstrates that Tau also plays a “good guy” role in glia by helping to sequester toxic lipids, reducing oxidative damage and, therefore, protecting our brain. However, when Tau is absent or when defective Tau proteins are present, this protective effect disappears, leading to disease.