Tau Proteins May Protect the Brain From Alzheimer's Disease

Tangles of tau proteins in the brain are a defining feature of Alzheimer's disease. Yet these important filaments have lately gained a ‘villain’ image that is not entirely warranted.

Tau’s story, much like Jekyll and Hyde, involves a complex balance between helpful and harmful roles.

Unexpected research in fly and rat brain cells indicates that tau proteins normally shield the brain against degeneration. They seem to play a part in brain disease only when they are missing or malfunctioning.

"By revealing a surprising new neuroprotective role for tau, the study opens the door to potential new strategies to slow, reverse, and treat neurodegenerative conditions," says neuroscientist Hugo Bellen from the Baylor College of Medicine in the US.

Tau proteins and fat droplets in the brain

The results lend weight to a possible root cause of Alzheimer's disease involving fat droplets within the brain’s connective tissue.

These fat droplets act rather like rubbish bags for neurological waste. When a neuron must dispose of harmful substances, including reactive oxygen species (ROS), it sends that waste to nearby cells known as glia. The glia then enclose the ROS within lipid droplets.

"This process effectively removes and neutralizes these toxic lipids," explains Lindsey Goodman, a neurobiologist at Bellen's lab.

However, when tau proteins are missing from fly glia, the lipid droplets fail to develop. Toxic ROS then builds up in the brain and causes motor defects.

Goodman and colleagues discovered that losing even 50 percent of healthy tau can interfere with lipid droplets and add to toxicity in fly brains.

Comparable effects occur in glial cells from rats and humans, suggesting that tau has a neuroprotective function in mammals, including humans.

The findings point to an additional advantage of tau. These proteins are plentiful in the human brain and, in their healthy form, fold and bind together to form an internal ‘skeleton’ for brain cells.

Defective tau and rising ROS levels

Difficulties arise when tau is absent or mutated, causing it to fold incorrectly.

Using a ‘humanised’ fly model carrying the tau mutations found in certain cases of Alzheimer's disease, the researchers showed that tau proteins were no longer able to counter increasing ROS levels.

When experiments raised ROS levels, flies with mutated tau experienced substantial damage to their glial cells.

The authors say the study offers "compelling evidence" that tau loss becomes harmful only in the presence of ROS. This may explain why mice genetically engineered to lack tau show no evidence of neurodegeneration until they reach old age, when ROS begins to accumulate.

Put another way, a shortage of healthy tau alone is not the sole source of trouble. What matters is the interaction between that shortage and a surge in toxic by-products in the brain.

"While low levels of ROS are beneficial, excess ROS is harmful to cells as it triggers the production of toxic forms of other molecules that induce oxidative stress," explains Goodman.

Alzheimer's disease treatments targeting tau

Over recent years, misfolded tau proteins have become recognised as one of the earliest biomarkers of Alzheimer's disease and can damage or kill neurons over time. Scientists are still working out, however, whether these tangles are a root cause of neurodegeneration or a response to another underlying problem.

Although Tau tangles occur in some brains of people who die with Alzheimer's, the mutated proteins cannot completely account for every subtype of this neurodegenerative disease.

Over the past 17 years, more than 30 medicines targeting tau have entered clinical trials after proving promising in animal models. So far, though, none has delivered benefits for human patients.

The latest study indicates that indiscriminately targeting every form of tau could remove the ‘good’ players as well as the ‘bad’ ones.

For tau-associated brain disease, nuance seems to be essential.

The study was published in Nature Neuroscience.