Using LEDs that can be programmed to flicker at different frequencies on mouse models genetically programmed to develop Alzheimer’s, researchers are exploring the potential of using light to reduce amyloid-β (Aβ) plaque levels and to stimulate brain waves that have been disrupted in Alzheimer patients. Professor Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory, is the senior author of the study, which appears in the Dec. 7 online edition of Nature. Courtesy of Bryce Vickmark. Aβ plaques, which are suspected to cause harm to brain cells, are a hallmark of Alzheimer’s disease. Studies have hinted that Alzheimer’s patients may also have impaired gamma oscillations. These brain waves are believed to contribute to normal brain functions such as attention, perception and memory. In a study of mice that did not yet show any plaque accumulation or behavioral symptoms, researchers at Massachusetts Institute of Technology (MIT) found impaired gamma oscillations during patterns of activity that are essential for learning and memory while running a maze. The researchers used an optogenetic technique to stimulate gamma oscillations at 40 Hz in the mouse hippocampus. After an hour of stimulation at 40 Hz, they found a 40 to 50 percent reduction in the levels of Aβ proteins in the hippocampus. Stimulation at other frequencies, ranging from 20 to 80 Hz, did not produce this decline. The initial study involved drilling a hole in the skull of the mouse and injecting a transgene-delivering virus into the brain. The researchers theorized that a less invasive technique might achieve the same effect, and decided to test the use of an external stimulus — LED light — to drive gamma oscillations in the mouse brain. To do so, they built a simple device consisting of a strip of LEDs that could be programmed to flicker at different frequencies. Using this device, the researchers found that an hour of exposure to light flickering at 40 Hz enhanced gamma oscillations and reduced Aβ levels by half in the visual cortex of mice in the very early stages of Alzheimer’s. However, the proteins returned to their original levels within 24 hours. The researchers then investigated whether a longer course of treatment could reduce Aβ plaques in mice with more advanced accumulation of Aβ plaques. After treating the mice for an hour a day for seven days, both plaques and free-floating amyloid were markedly reduced. The researchers are now trying to determine how long these effects will last. The research team further found that gamma rhythms also reduced abnormal modifications to Tau protein, another indicator of Alzheimer’s disease. Gamma oscillations also improved the “housekeeping” ability of the brain’s immune cells, microglia, to clear out Aβ proteins. "They take up toxic materials and cell debris, clean up the environment, and keep neurons healthy," said Li-Huei Tsai, director of the Picower Institute for Learning and Memory. The researchers are now studying whether light can drive gamma oscillations in brain regions beyond the visual cortex, and preliminary data suggest that this is possible. They are also investigating whether the reduction in amyloid plaques has any effect on the behavioral symptoms of their Alzheimer's mouse models, and whether their technique would have an effect other neurological disorders that involve impaired gamma oscillations. "The bottom line is, enhancing gamma oscillations in the brain can do at least two things to reduce amyloid load. One is to reduce beta amyloid production from neurons. And second is to enhance the clearance of amyloids by microglia," said Tsai. Tsai noted that further research will be needed to determine if a similar approach could help Alzheimer's patients. "It's a big 'if,' because so many things have been shown to work in mice, only to fail in humans," she said. "But if humans behave similarly to mice in response to this treatment, I would say the potential is just enormous, because it's so noninvasive, and it's so accessible." The research was published in Nature (doi: 10.1038/nature20587). Researchers in Li-Huei Tsai's laboratory at the Picower Institute for Learning and Memory have shown that disrupted gamma waves in the brains of mice with Alzheimer’s disease can be corrected by a unique non-invasive technique using flickering light. Courtesy of The Picower Institute for Learning and Memory.