A New Role Discovered for Tau: Protecting the Brain from Oxidative Stress

Excess reactive oxygen species or free radicals (ROS) are a common feature of neurodegenerative diseases like Alzheimer’s disease. A recent study by postdoctoral associate Dr. Lindsey Goodman and Dr. Hugo Bellen, a distinguished service professor in Molecular Biology and Genetics at Baylor College of Medicine, who also holds a Chair in Neurogenetics at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital, have discovered an important role for the disease-associated protein, Tau, in mitigating damage to the brain caused by excessive ROS and in promoting healthy aging. The study was recently published in Nature Neuroscience.

“By revealing a surprising new neuroprotective role for Tau protein – a key player implicated in several neurodegenerative conditions including Alzheimer’s disease – the study opens the door to potential new avenues and therapeutic strategies to slow, reverse, and treat neurodegenerative conditions,” said Dr. Bellen who is also a March of Dimes Professor in Developmental Biology at Baylor College of Medicine.

Excess free radicals damage neurons

Free radicals or reactive oxygen species (ROS) are unstable molecules with unpaired electrons that seek electrons to pair from other molecules, thus damaging those molecules and nearby tissues in the process. ROS is a natural byproduct of various cellular reactions in the body and low levels of ROS are beneficial. However, excess ROS is harmful to cells with aberrantly high ROS levels being generated in response to many environmental insults including microbial infections, fatty diets, and exposure to toxins such as tobacco smoke, ultraviolet rays, air pollution, etc. Excess ROS triggers the production of toxic forms of molecules including peroxidated lipids, damaging cells while inducing oxidative stress.

Neurons are particularly susceptible to oxidative stress and are destroyed if peroxidated lipid levels are not tightly controlled. Since lipids make up 60% of brain cells by dry weight, it is unsurprising that the health and function of the brain cells are closely tied to lipid homeostasis.

Lipid droplets protect the brain from oxidative damage

There is mounting evidence supporting the notion that our brains have developed multiple neuroprotective strategies to combat ROS-induced oxidative damage.

Studies in the past decade by the Bellen Lab and others have found a new neuroprotective mechanism by which glia (non-neuron brain cells) help to protect neurons from these toxic peroxidated lipids. In 2015, the Bellen team discovered that these toxic lipids are exported to neighboring glial cells and sequestered into lipid droplets (LDs) for storage and future energy production.

Lipid droplets are evolutionarily conserved organelles employed by many cell types including glia to stockpile lipids and this can be triggered under conditions of cellular stress such as a high-fat diet, inflammation, altered oxygen levels, etc. They are composed of a hydrophobic

core of neutral lipids surrounded by a phospholipid monolayer that is decorated with proteins to sense external conditions and release the stored lipids as needed. Lipid droplets interact with organelles in a cell to promote the breakdown of the lipids they contain while producing energy. In the case of peroxidated lipids contained within lipid droplets, this process effectively removes these toxic lipids from the cell stopping them from causing damage.

Lipid droplets play important roles during development, aging, and in neuropathologies. Recent studies have found a growing number of Alzheimer’s disease-risk-associated genes are associated with the formation and function of lipid droplets in the glia, suggesting that defects in this pathway contribute to disease progression.

Pathogenic human Tau prevents the formation of glial lipid droplets in flies and mice

Disruptions in the microtubule-associated Tau protein are a hallmark of aging and several neurodegenerative conditions such as Alzheimer’s disease and are often associated with overexpression of aberrant and toxic forms of Tau protein in the brain. “We found that overexpressing the disease-causing versions of human Tau protein (which are linked to an increased risk for Alzheimer’s disease) in glia but not in neurons, inhibited the ability for the glia to form lipid droplets in response to neuronal ROS. This led to the demise of the glia,” lead author, Dr. Lindsey Goodman who is a postdoctoral fellow in the Bellen lab, said.

Glial Tau is crucial for the formation of lipid droplets and to counteract toxicity due to neuronal ROS

While previous research has highlighted Tau’s critical functions in neurons, the Bellen team found that endogenous Tau protein is also important in glia. Flies lacking Tau in glia showed signs of degeneration such as progressive motor defects and decreased lifespans. Interestingly, these flies build up peroxidated lipids in their brains and treating them with an antioxidant, N-acetylcysteine amide, can prevent the motor defects caused by Tau loss in glia.

“We also found that endogenous Tau in flies is required for glial lipid droplet formation and for protecting against neuronal ROS. Similarly, Tau was required in glial cells obtained from rats and humans to form lipid droplets,” said Dr. Goodman.

Specifically, they found that the Tau protein in fly and mammalian glia played an important role during the formation and maturation of lipid droplets. These lipid droplets counteract oxidative stress and toxicity associated with neuronal ROS. Hence, Tau is important for protecting against ROS in the brain.

Finally, while expression of wild-type human tau was sufficient to restore the process of formation and maturation of glial lipid droplets in flies lacking their endogenous Tau, mutant forms of human Tau were unable to do so. “This argues that mutations in Tau may reduce the protein’s normal ability to prevent oxidative stress in addition to causing the protein to accumulate into the pathological hallmarks of disease as described by previous work,” said Dr. Goodman.

In conclusion, contrary to its usual ‘bad guy’ role in neurodegenerative disease, this study demonstrates Tau protein in the glia helps sequester toxic lipids, reduces the oxidative damage to glia, and hence, acts as a ‘good guy’ to protect our brains. The lack of Tau or the bad forms of Tau are those that fail to protect.