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Light vs. Alzheimer's?
CAMBRIDGE, Mass.—It's known that flickering lights can negatively impact neurological conditions such as epilepsy by triggering a seizure, but research out of the Massachusetts Institute of Technology (MIT) is demonstrating that flickering light can help in other situations. In work that was first announced in 2016, and has been expanded on this week, scientists have found that light flickering at a certain frequency—40 hertz, to be precise—can diminish amyloid plaques in mouse models of Alzheimer's disease, in addition to boosting synaptic function and protecting against cell death. The latest in this work was published online in Neuron on May 7, in an article titled “Gamma Entrainment Binds Higher-Order Brain Regions and Offers Neuroprotection.”
The original research, published in December 2016, explained that flickering LED lights at the 40 hertz frequency induces gamma oscillations, brain waves that help to suppress the production of beta amyloid and also boost microglia, the cells that clear out the amyloid plaques Alzheimer's disease is known for. Previous research has implied that Alzheimer's patients present with impaired gamma oscillations, which play a role in brain functions such as attention, memory and perception. When the researchers stimulated gamma oscillations in the hippocampus using optogenetics, they found that after an hour, beta amyloid proteins had decreased by 40 to 50 percent.
They then tried to recreate the effects with a less invasive approach, engineering a strip of LED lights to flicker at the appropriate frequency. When tested, it proved to decrease beta amyloid levels by half in the visual cortex of mice, but protein levels returned to the original level within a day. Treatment for an hour a day for a week led to a significant reduction in free amyloid and plaques, as well as abnormal Tau proteins, which can form the neurofibrillary tangles that characterize Alzheimer's disease.
The next step saw the research team exploring ways to engender these benefits in regions of the brain beyond the visual cortex, results that were reported on earlier this year. By exposing the mice to 40-hertz tones for one hour a day for a week, beta amyloid levels in the auditory cortex and hippocampus dropped. When the lights and tones were combined, amyloid plaques “were reduced throughout a much greater portion of the brain, including the prefrontal cortex, where higher cognitive functions take place. The microglia response was also much stronger,” according to a March 2019 press release by MIT's Anne Trafton.
The downside to these results was that similar to the work done in 2016, the effects seem to fade after time, so if this could be replicated in humans, it would require frequent, regular treatment.
“It’s a big ‘if,’ because so many things have been shown to work in mice, only to fail in humans,” Li-Huei Tsai, the Picower Professor of Neuroscience, director of MIT’s Picower Institute for Learning and Memory, and senior author of the study, said in a 2016 press release regarding the original work. “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.”
Work is now underway to evaluate that “if” and see whether or not these results can be replicated in people. The combined lights and tones approach has been tested in healthy individuals, and enrollment is underway for a study of patients with early-stage Alzheimer's disease.
The most recent stage of the research, published this week in Neuron, saw the scientists looking more closely at where in the brain this treatment produces such encouraging results.
To start with, this latest round of work utilized two mouse strains that are genetically engineered to develop Alzheimer's disease—and specifically, present with more neuron loss than the mice used in the original study, according to Tsai. One mouse strain, Tau P301S, has a mutated form of the Tau protein that results in neurofibrillary tangles, while the other, CK-p25, produces the p25 protein, which leads to severe neurodegeneration. In both strains, the flickering light treatment—administered one hour a day for three to six weeks—decreased or prevented neurodegeneration.
This study also examined the response of microglia to the light treatment. Microglia become inflammatory in Alzheimer's disease pathology, increasing their expression of inflammation-promoting genes and secreting toxic chemicals, as noted in a press release by Trafton. In the mice that received the light treatment, expression of those genes was decreased, and levels of the form of Tau that leads to neurofibrillary tangles were reduced as well.
“Tau P301S and CK-p25 mice subjected to chronic, daily GENUS from the early stages of neurodegeneration showed a preservation of neuronal and synaptic density across multiple brain areas and modified cognitive performance,” the authors noted in the Neuron paper. “Our transcriptomic and phosphoproteomic data suggest that chronic GENUS shifts neurons to a less degenerative state, improving synaptic function, enhancing neuroprotective factors, and reducing DNA damage in neurons while also reducing inflammatory response in microglia. ”
Exactly how gamma oscillations induces these benefits is still unknown, according to Tsai.
“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,” she remarked. “After all, oscillations are initiated by neurons, and I still like to think that they are the master regulators. I think the oscillation itself must trigger some intracellular events, right inside neurons, and somehow they are protected.”