Tau protein shows unexpected benefits in mitigating brain damage

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

“ROS are natural byproducts of various cellular functions in the body. While low levels of ROS are beneficial, excess ROS is harmful to cells by causing the production of toxic forms of other molecules that cause oxidative stress, including peroxidized lipids,” said the leader. author Dr. Lindsey Goodman, a postdoctoral researcher in Dr. Hugo Bellen. “Neurons are particularly sensitive to oxidative stress and are destroyed if peroxidized lipid levels are not tightly controlled.”

Lipid droplets protect the brain against oxidative damage

There is increasing evidence to support the idea that our brains have developed multiple neuroprotective strategies to combat ROS-induced oxidative damage.

One of the strategies, discovered in 2015 by the Bellen team, involves neurons exporting these toxic peroxidized lipids to neighboring glial cells, which lock them in lipid droplets for storage and future 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 endogenous normal Tau in flies is required for the formation of glial lipid droplets and for protection against neuronal ROS. Similarly, Tau 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 this human Tau protein carried disease-causing mutations – linked to an increased risk of the disease of Alzheimer’s – the glia were unable to form lipid droplets in response to neuronal ROS.

This argues that mutations in Tau can reduce the protein’s normal ability to prevent oxidative stress and additionally cause the protein to accumulate the hallmarks of disease, as described in previous work. Taken together, the findings support a novel neuroprotective role for Tau against the toxicity associated with ROS.”

Dr. Lindsey Goodman, lead author

Further links to disease were discovered using established fly and rat models of Tau-mediated disorders that overexpress disease-causing human Tau proteins 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 dose-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, corresponding author of the work. He is a distinguished service professor in molecular biology and genetics at Baylor and holds a chair in neurogenetics at Duncan NRI. Bellen is also the March of Dimes Professor of Developmental Biology at Baylor.

In summary, in contrast to the usual ‘bad guy’ role in neurodegenerative diseases, this study shows that Tau also plays a ‘good guy’ role in glia by helping to store toxic lipids, reducing oxidative damage and thus protecting our brains . However, when Tau is absent or when defective Tau proteins are present, this protective effect disappears, leading to disease.