Researchers have previously shown that a type of light therapy could potentially reduce toxic proteins that build up in the brain in Alzheimer's disease. Now, the same team has identified what happens at cell level to achieve this result.

In 2016, scientists at Massachusetts Institute of Technology (MIT) in Cambridge found that shining a flickering light into the eyes of mice could reduce the toxic buildup of amyloid and tau proteins that occur in the brain with Alzheimer's disease. Light therapy boosts a form of brain wave called gamma oscillation, which research suggests is impaired in people with Alzheimer's disease. More recently, the MIT team revealed that combining light therapy with sound therapy extended the beneficial effects even further.

Those studies also showed that light therapy can improve memory in mice genetically predisposed to develop Alzheimer's disease and spatial memory in older mice without the condition.

The most recent investigation, which now features in the journal Neuron, has shown that boosting gamma oscillations can improve the connection between nerve cells, reduce inflammation, and protect against cell death in mouse models of Alzheimer's. It also shows that the treatment's far-reaching effects involve not only nerve cells, or neurons, but also a type of immune cell called microglia. "It seems," says senior study author Li-Huei Tsai, a professor of neuroscience and director of the Picower Institute for Learning and Memory at MIT, "that neurodegeneration is largely prevented."

Alzheimer's and toxic proteins

Alzheimer's is a condition that gradually destroys brain tissue and associated function through the irreversible loss of cells. A 2018 report by Alzheimer's Disease International reveals that 50 million people worldwide have dementia, and that for two-thirds of them, Alzheimer's disease is the cause.

Although some treatments can slow Alzheimer's symptoms down for a while, none, as yet, can cure the condition. In people with Alzheimer's disease, the brain begins to change a long time before they experience symptoms of dementia. Such symptoms include difficulties with thinking and remembering.

Two changes in particular are the development of toxic deposits, or plaques, of beta-amyloid protein between nerve cells, and the formation of toxic tangles of tau protein inside the cells.

Tsai and her colleagues explain that people with Alzheimer's disease also show another alteration in the brain: "reduced power of oscillations in the gamma frequency band."

Scientists have proposed that gamma oscillations are a type of brain wave important for functions such as memory and attention. In their earlier work, the researchers had shown that exposure to light flickering at a rate of 40 cycles per second, or hertz, stimulated gamma oscillations in the visual cortex of the brain in mice. Adding sound tones beating at the same frequency enhanced the plaque-reducing effect of the light therapy and extended it beyond the visual cortex into the hippocampus and some of the prefrontal cortex. Gamma oscillations from both treatments also led to improvements in memory function in mouse models of Alzheimer's disease.

Remarkable level of neuroprotection

With the new study, the researchers wanted to find out more about the underlying mechanisms that led to these benefits. To do so, they used two mouse models of Alzheimer's: Tau P301S and CK-p25. Tsai says that both types of mice experience much greater loss of nerve cells than the model that they used in the earlier light therapy studies.

Tau P301S mice produce a mutant tau protein that forms tangles inside cells such as those that occur inside brain cells of humans with Alzheimer's disease. CK-p25 mice produce a protein called p25 that causes "severe neurodegeneration."

The team saw that daily light therapy that began before the anticipated start of neurodegeneration produced remarkable effects on both types of mice. Tau P301S mice that received 3 weeks of treatment showed no signs of neuron degeneration, compared with 15%–20% neuron loss in the untreated mice. The result was the same in the CK-p25 mice, which underwent 6 weeks of treatment.

Tsai claims that she has "been working with p25 protein for over 20 years," and the protein is very toxic to the brain. However, she has never seen anything like this result before. "It's very shocking," she adds. "We found that the p25 transgene expression levels are exactly the same in treated and untreated mice, but there is no neurodegeneration in the treated mice," she explains.

When the researchers tested the mice's spatial memory, they also found surprising results: Light therapy improved performance in older mice that were not genetically programmed to develop Alzheimer's disease, but it had no effect on younger, similar mice.

Marked differences in gene activity

The researchers also examined gene changes in the treated and untreated mice. They found that the nerve cells of untreated mice had reduced activity in genes that repair DNA and in those that help operate the connections between nerve cells. The treated mice, on the other hand, showed greater activity in these genes.

Also, they saw that the treated mice had more connections between nerve cells, and that these operated more coherently. The scientists also investigated gene activity in the microglia, or immune cells, that help clear away cell waste and other debris in the brain. Those investigations revealed that genes that promote inflammation were more active in mice that did not receive the light therapy. However, treated mice showed a marked lack of activity in these genes. They also showed increased activity in genes that affect the ability of microglia to move around.

The study authors explain that these findings suggest that light therapy strengthened the ability of microglia to deal with inflammation. Perhaps it made them better able to clear away waste materials, including faulty proteins that can accumulate to form toxic plaques and tangles.

Tsai reminds us that one important question still has no answer: How does gamma oscillation induce these various forms of protection? Perhaps the oscillations set off something inside nerve cells. Tsai says she likes to think that nerve cells are "the master regulators."

"A lot of people have been asking me whether the microglia are the most important cell type in this beneficial effect, but to be honest, we really don't know."

—Professor Li-Huei Tsai