Studies at MIT and elsewhere are producing mounting evidence that light flickering and sound clicking at the gamma brain rhythm frequency of 40 Hz can reduce Alzheimer’s disease (AD) progression and treat symptoms in human volunteers as well as lab mice. In a new study in Nature using a mouse model of the disease, researchers at The Picower Institute for Learning and Memory of MIT reveal a key mechanism that may contribute to these beneficial effects: clearance of amyloid proteins, a hallmark of AD pathology, via the brain’s glymphatic system, a recently discovered “plumbing” network parallel to the brain’s blood vessels.
“Ever since we published our first results in 2016, people have asked me how does it work? Why 40 Hz? Why not some other frequency?” said study senior author Li-Huei Tsai, Picower Professor of Neuroscience and director of The Picower Institute and MIT’s Aging Brain Initiative. “These are indeed very important questions we have worked very hard in the lab to address.”
The new paper describes a series of experiments, led by Mitch Murdock when he was a Brain and Cognitive Sciences doctoral student at MIT, showing that when sensory gamma stimulation increases 40 Hz power and synchrony in the brains of mice, that prompts a particular type of neuron to release peptides. The study results further suggest that those short protein signals then drive specific processes that promote increased amyloid clearance via the glymphatic system.
“We do not yet have a linear map of the exact sequence of events that occurs,” said Murdock, who was jointly supervised by Tsai and co-author and collaborator Ed Boyden, Y. Eva Tan Professor of Neurotechnology at MIT, a member of the McGovern Institute for Brain Research and an affiliate member of The Picower Institute. “But the findings in our experiments support this clearance pathway through the major glymphatic routes.”
From Gamma to Glymphatics
Because prior research has shown that the glymphatic system is a key conduit for brain waste clearance and may be regulated by brain rhythms, Tsai and Murdock’s team hypothesized that it might help explain the lab’s prior observations that gamma sensory stimulation reduces amyloid levels in Alzheimer’s model mice.
Working with “5XFAD” mice, which genentically model Alzheimer’s, Murdock and co-authors first replicated the lab’s prior results that 40 Hz sensory stimulation increases 40 Hz neuronal activity in the brain and reduces amyloid levels. Then they set out to measure whether there was any correlated change in the fluids that flow through the glymphatic system to carry away wastes. Indeed, they measured increases in cerebrospinal fluid in the brain tissue of mice treated with sensory gamma stimulation compared to untreated controls. They also measured an increase in the rate of interstitial fluid leaving the brain. Moreover, in the gamma-treated mice he measured increased diameter of the lymphatic vessels that drain away the fluids and measured increased accumulation of amyloid in cervical lymph nodes, which is the drainage site for that flow.
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