Scientists Find New Role of Tau Protein: Boosting Brain Health and Aging
tau protein brain health aging
A recent investigation has uncovered that the Tau protein, traditionally associated with neurodegenerative disorders, also plays a crucial role in safeguarding the brain by managing toxic lipids within glial cells. This finding hints at promising avenues for novel therapeutic approaches to these diseases.
Scientists at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital have found that Tau, typically linked to conditions like Alzheimer’s, exhibits protective functions in the brain.
Their research, published in Nature Neuroscience, reveals that Tau mitigates neuronal damage by regulating excessive reactive oxygen species (ROS), also known as free radicals, thereby promoting healthy aging.
“ROS are natural byproducts of cellular processes in the body. While small quantities are beneficial, an excess can be detrimental, generating toxic molecules that trigger oxidative stress, including peroxidated lipids,” explained Dr. Lindsey Goodman, lead author and postdoctoral fellow in the lab of Dr. Hugo Bellen.
“Neurons are highly vulnerable to oxidative stress and may be destroyed if the levels of peroxidated lipids are not strictly controlled.”
Lipid droplets shield the brain from oxidative harm
The brain employs several neuroprotective mechanisms to counteract ROS-induced oxidative damage, a notion increasingly supported by evidence.
In 2015, Bellen’s team uncovered a process whereby neurons offload toxic peroxidated lipids to neighboring glial cells. These cells then encapsulate the lipids into droplets for storage and potential future energy use.
“This mechanism effectively neutralizes these harmful lipids,” said Goodman. “In our current research, we explored the involvement of Tau in the formation of these lipid droplets in glial cells.”
The team demonstrated that normal Tau in flies is necessary for the formation of lipid droplets in glial cells and for shielding neurons from ROS. Similarly, Tau was essential in glial cells derived from rats and humans for lipid droplet formation.
While the expression of human Tau was enough to restore the lipid droplet formation process in Tau-deficient flies, introducing a mutated form of the human Tau protein — linked to an increased risk of Alzheimer’s — led to a failure in lipid droplet formation in response to neuronal ROS.
“This suggests that mutations in Tau may not only hinder its ability to prevent oxidative stress but also contribute to the protein’s accumulation, a hallmark of neurodegenerative diseases,” noted Goodman.
“Collectively, our results highlight a neuroprotective role for Tau in mitigating ROS-induced toxicity.”
Further research, using established fly and rat models of Tau-related conditions, revealed additional defects in glial lipid droplet formation and cell death in response to neuronal ROS.
This illustrated that Tau acts as a dosage-sensitive regulator of lipid droplets in glial cells, where both an excess or deficiency of Tau can have harmful consequences.
“Unveiling this unexpected neuroprotective function of Tau opens the door to potential treatments aimed at slowing or even reversing the progression of neurodegenerative diseases,” remarked Bellen, the study’s corresponding author and distinguished service professor of molecular biology and genetics at Baylor.
He also holds a Chair in Neurogenetics at Duncan NRI and serves as a March of Dimes Professor in Developmental Biology at Baylor.
In conclusion, this study demonstrates that Tau, contrary to its typical association with disease, also plays a beneficial role by helping glial cells sequester toxic lipids, thereby reducing oxidative stress and protecting brain function.
However, when Tau is absent or when defective Tau proteins are present, this protective mechanism is impaired, leading to neurodegenerative conditions.
Reference
“Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress” by Lindsey D. Goodman, Isha Ralhan, Xin Li, Shenzhao Lu, Matthew J. Moulton, Ye-Jin Park, Pinghan Zhao, Oguz Kanca, Ziyaneh S. Ghaderpour Taleghani, Julie Jacquemyn, Joshua M. Shulman, Kanae Ando, Kai Sun, Maria S. Ioannou, and Hugo J. Bellen, 26 August 2024, Nature Neuroscience. DOI: 10.1038/s41593-024-01740-1
This research was funded by grants from the National Institutes of Health, the Canadian Institutes of Health, and Research Doctoral Award, the Sloan Research Fellowship from the Alfred P. Sloan Foundation, the Canada Research Chairs program, a CIHR project grant, and a Grant-in-Aid for Scientific Research on Challenging Research (Exploratory).
