A path for addressing Alzheimer’s blood-brain barrier impairment

Brain's "keep out" system is compromised in Alzheimer's disease
Research Paper
artistic painting representing brain blood vessels
Detail from a painting by co-author Leyla Akay inspired by the paper.

By developing a lab-engineered model of the human blood-brain barrier (BBB), neuroscientists at MIT’s Alana Down Syndrome Center have discovered how the most common Alzheimer’s disease risk gene causes amyloid protein plaques to disrupt the brain’s vasculature and showed they could prevent the damage with medications already approved for human use.

About 25 percent of people have the APOE4 variant of the APOE gene, which puts them at substantially greater risk for Alzheimer’s disease. Almost everyone with Alzheimer’s, and even some elderly people without, suffer from cerebral amyloid angiopathy (CAA), a condition in which amyloid protein deposits on blood vessel walls impairs the ability of the BBB to properly transport nutrients, clear out waste and prevent the invasion of pathogens and unwanted substances.

In the new study, published June 8 in Nature Medicine, the researchers pinpointed the specific vascular cell type (pericytes) and molecular pathway (calcineurin/NFAT) through which the APOE4 variant promotes CAA pathology.

The research indicates that in people with the APOE4 variant, pericytes in their vessels churn out too much APOE protein, explained senior author Li-Huei Tsai, Picower Directory & Professor of Neuroscience and co-Director of the Alana Down Syndrome Center. APOE causes amyloid proteins, which are more abundant in Alzheimer’s disease, to clump together. Meanwhile, the diseased pericytes’ increased activation of the calcineurin/NFAT molecular pathway appears to encourage the elevated APOE expression.

There are already drugs that suppress the pathway. Currently they are used to subdue the immune system after a transplant. When the researchers administered some of those drugs, including cyclosporine A and FK506, to the lab-grown BBBs with the APOE4 variant, they accumulated much less amyloid than untreated ones did.

“We identify that there is a specific genetic pathway that is expressed differently in a population that is susceptible to Alzheimer’s disease,” said study lead author Joel Blanchard, a postdoc in Tsai’s lab. “By identifying this we could identify drugs that change this pathway back to a non-diseased state and correct this outcome that’s associated with Alzheimer’s.”

Building barriers

To investigate the connection between Alzheimer’s, the APOE4 variant and CAA, Blanchard, Tsai and co-authors coaxed human induced pluripotent stem cells to become the three types of cells that make up the BBB: brain endothelial cells, astrocytes and pericytes. Pericytes were modeled by mural cells that they tested extensively to ensure they exhibited pericyte-like properties and gene expression.

Grown for two weeks within a three-dimensional hydrogel scaffold, the BBB model cells assembled into vessels that exhibited natural BBB properties, including low permeability to molecules and expression of the same key genes, proteins and molecular pumps as natural BBBs. When immersed in culture media high in amyloid proteins, mimicking conditions in Alzheimer’s disease brains, the lab-grown BBB models exhibited the same kind of amyloid accumulation seen in human disease.

With a model BBB established, they then sought to test the difference APOE4 makes. They showed by several measures that APOE4-carrying BBB models accumulated more amyloid from culture media than those carrying APOE3, the more typical and healthy variant.

To pinpoint how APOE4 makes that difference, they engineered eight different versions covering all the possible combinations of the three cell types having either APOE3 or APOE4. When exposed these month-old models to amyloid-rich media, only versions with APOE4 pericyte-like mural cells showed excessive accumulation of amyloid proteins. Replacing APOE4 mural cells with APOE3-carrying ones reduced amyloid deposition. These results put blame for CAA-like pathology squarely on pericytes.

To further validate the clinical relevance of these findings, the team also looked at APOE expression in samples of human brain vasculature in the prefrontal cortex and the hippocampus, two regions crucially affected in Alzheimer’s disease. Consistent with the team’s lab BBB model, people with APOE4 showed higher expression of the gene in the vasculature, and specifically in pericytes, than people with APOE3.

“That is a salient point of this paper,” said Tsai. “It’s really cool because it stresses the cell-type specific function of APOE.”

A pathway toward treatment?

The next step was to determine how APOE4 becomes so overexpressed by pericytes. The team therefore identified hundreds of transcription factors – proteins that determine how genes are expressed – that were regulated differently between APOE3 and APOE4 pericyte-like mural cells. Then they scoured that list to see which factors specifically impact APOE expression. A set of factors that were upregulated in APOE4 cells stood out: ones that were part of the calcineurin/NFAT pathway. They observed similar upregulation of the pathway in pericytes from human hippocampus samples.

As part of their investigation of whether elevated signaling activity of this pathway caused increased amyloid deposition and CAA, they tested cyclosporine A and FK506 because they tamp pathway activity down. They found that the drugs reduced APOE expression in their pericyte-like mural cells and therefore APOE4-mediated amyloid deposits in the BBB models. They also tested the drugs in APOE4-carrying mice and saw that the medicines reduced APOE expression and amyloid buildup.

Blanchard and Tsai noted that the drugs can have significant side effects, so their findings might not suggest using exactly those drugs to address CAA in patients.

“Instead it points toward the value of understanding the mechanism,” Blanchard said. “It allows one to design a small molecule screen to find more potent drugs that have less off-target effects.”

In addition to Blanchard and Tsai, the paper’s other authors are Michael Bula, Jose Davila-Velderrain, Leyla Akay, Lena Zhu, Alexander Frank, Matheus Victor, Julia Maeve Bonner, Hansruedi Mathys, Yuan-Ta Lin, Tak Ko, David Bennett, Hugh Cam, and Manolis Kellis.

The Robert A. and Renee E. Belfer Family Foundation, the Cure Alzheimer’s Fund, The National Institutes of Health, the Glenn Foundation for Medical Research and the American Federation for Aging Research funded the research.

Written by David Orenstein, Picower Institute for Learning and Memory

New method visualizes groups of neurons as they compute

Fluorescent probe could allow scientists to watch circuits within the brain and link their activity to specific behaviors.
Research Paper
A colorfully stained image of a hippocampus
Neurons in a mouse brain are labeled purple. In green, neurons are labeled with a fluorescent probe that reveals electrical activity.

Using a fluorescent probe that lights up when brain cells are electrically active, MIT and Boston University researchers have shown that they can image the activity of many neurons at once, in the brains of mice.

This technique, which can be performed using a simple light microscope, could allow neuroscientists to visualize the activity of circuits within the brain and link them to specific behaviors, says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology and a professor of biological engineering and of brain and cognitive sciences at MIT.

“If you want to study a behavior, or a disease, you need to image the activity of populations of neurons because they work together in a network,” says Boyden, who is also a member of MIT’s McGovern Institute for Brain Research, Media Lab, and Koch Institute for Integrative Cancer Research, and is a member of the Alana Down Syndrome Center.

Using this voltage-sensing molecule, the researchers showed that they could record electrical activity from many more neurons than has been possible with any existing, fully genetically encoded, fluorescent voltage probe.

Boyden and Xue Han, an associate professor of biomedical engineering at Boston University, are the senior authors of the study, which appears in the Oct. 9 online edition of Nature. The lead authors of the paper are MIT postdoc Kiryl Piatkevich, BU graduate student Seth Bensussen, and BU research scientist Hua-an Tseng.

Seeing connections

Neurons compute using rapid electrical impulses, which underlie our thoughts, behavior, and perception of the world. Traditional methods for measuring this electrical activity require inserting an electrode into the brain, a process that is labor-intensive and usually allows researchers to record from only one neuron at a time. Multielectrode arrays allow the monitoring of electrical activity from many neurons at once, but they don’t sample densely enough to get all the neurons within a given volume.  Calcium imaging does allow such dense sampling, but it measures calcium, an indirect and slow measure of neural electrical activity.

In 2018, Boyden’s team developed an alternative way to monitor electrical activity by labeling neurons with a fluorescent probe. Using a technique known as directed protein evolution, his group engineered a molecule called Archon1 that can be genetically inserted into neurons, where it becomes embedded in the cell membrane. When a neuron’s electrical activity increases, the molecule becomes brighter, and this fluorescence can be seen with a standard light microscope.

In the 2018 paper, Boyden and his colleagues showed that they could use the molecule to image electrical activity in the brains of transparent worms and zebrafish embryos, and also in mouse brain slices. In the new study, they wanted to try to use it in living, awake mice as they engaged in a specific behavior.

To do that, the researchers had to modify the probe so that it would go to a subregion of the neuron membrane. They found that when the molecule inserts itself throughout the entire cell membrane, the resulting images are blurry because the axons and dendrites that extend from neurons also fluoresce. To overcome that, the researchers attached a small peptide that guides the probe specifically to membranes of the cell bodies of neurons. They called this modified protein SomArchon.

microscope image of neurons from mouse cortex, hippocampus and striatum
MIT researchers developed a light-sensitive protein that can be embedded into neuron membranes, where it emits a fluorescent signal that indicates how much voltage a particular cell is experiencing. Microscope images of SomArchon-expressing neurons in cortex layer 2/3 (left), hippocampus (middle), and striatum (right)

“With SomArchon, you can see each cell as a distinct sphere,” Boyden says. “Rather than having one cell’s light blurring all its neighbors, each cell can speak by itself loudly and clearly, uncontaminated by its neighbors.”

The researchers used this probe to image activity in a part of the brain called the striatum, which is involved in planning movement, as mice ran on a ball. They were able to monitor activity in several neurons simultaneously and correlate each one’s activity with the mice’s movement. Some neurons’ activity went up when the mice were running, some went down, and others showed no significant change.

“Over the years, my lab has tried many different versions of voltage sensors, and none of them have worked in living mammalian brains until this one,” Han says.

Using this fluorescent probe, the researchers were able to obtain measurements similar to those recorded by an electrical probe, which can pick up activity on a very rapid timescale. This makes the measurements more informative than existing techniques such as imaging calcium, which neuroscientists often use as a proxy for electrical activity.

“We want to record electrical activity on a millisecond timescale,” Han says. “The timescale and activity patterns that we get from calcium imaging are very different. We really don’t know exactly how these calcium changes are related to electrical dynamics.”

With the new voltage sensor, it is also possible to measure very small fluctuations in activity that occur even when a neuron is not firing a spike. This could help neuroscientists study how small fluctuations impact a neuron’s overall behavior, which has previously been very difficult in living brains, Han says.

Mapping circuits

The researchers also showed that this imaging technique can be combined with optogenetics— a technique developed by the Boyden lab and collaborators that allows researchers to turn neurons on and off with light by engineering them to express light-sensitive proteins. In this case, the researchers activated certain neurons with light and then measured the resulting electrical activity in these neurons.

This imaging technology could also be combined with expansion microscopy, a technique that Boyden’s lab developed to expand brain tissue before imaging it, make it easier to see the anatomical connections between neurons in high resolution.

“One of my dream experiments is to image all the activity in a brain, and then use expansion microscopy to find the wiring between those neurons,” Boyden says. “Then can we predict how neural computations emerge from the wiring.”

Such wiring diagrams could allow researchers to pinpoint circuit abnormalities that underlie brain disorders, and may also help researchers to design artificial intelligence that more closely mimics the human brain, Boyden says.

The MIT portion of the research was funded by Edward and Kay Poitras, the National Institutes of Health, including a Director’s Pioneer Award, Charles Hieken, John Doerr, the National Science Foundation, the HHMI-Simons Faculty Scholars Program, the Human Frontier Science Program, and the U.S. Army Research Office.

 

By

Ann Trafton, MIT News Office

Study helps explain varying outcomes for cancer, Down Syndrome

Differences in chromosome number may underlie variation among genetically identical individuals
Research Paper
A yellow to blue heat map
Colors represent variability of responses by cells with extra chromosomes

Aneuploidy is a condition in which cells contain an abnormal number of chromosomes, and is known to be the cause of many types of cancer and genetic disorders, including Down Syndrome. The condition is also the leading cause of miscarriage.

Disorders caused by aneuploidy are unusual in that the severity of their effects often varies widely from one individual to another.

For example, nearly 90 percent of fetuses with three copies of chromosome 21, the cause of Down Syndrome, will miscarry before birth. In other cases, people with the condition will live until they are over 60 years old.

Researchers have previously believed that this variation is the result of differences in the genetic makeup of those individuals with the condition.

But in a paper published today in the journal Cell, researchers at MIT reveal that aneuploidy alone can cause this significant variability in traits, in otherwise genetically identical cells.

The finding could have significant implications for cancer treatment, since it could explain why genetically identical cancer cells may respond differently to the same therapy.

An immediate impact

Aneuploidy originates during cell division, when the chromosomes do not separate properly or are not equally partitioned between the two daughter cells. This leads the cells, which in humans would normally have 46 chromosomes, to develop with either too many or too few chromosomes.

To study the effects of the condition, the researchers induced either chromosome loss or gain in genetically identical baker’s yeast cells. They chose baker’s yeast because the cells behave in a very similar way to human cells, according to Angelika Amon, the Kathleen and Curtis Marble Professor of Cancer Research, co-Director of the Alana Down Syndrome Center, and a member of the Koch Institute.

The induced changes had an immediate impact on the cells.

“We induced aneuploidy, and we found that the response was very variable from cell to cell,” Amon says. “Some cells slowed down their cycle completely, so that they could no longer divide, whereas others kept dividing quite normally and only experienced a small effect.”

The researchers carried out a systematic analysis, investigating the effect on the cells of gaining or losing a variety of different chromosomes. They found that in each case, even though individual cells had gained or lost the same chromosome, they behaved very differently from each other.

“So that really suggested that every single chromosome gained or lost had this effect, in that the responses (in each case) were quite variable,” Amon says.

Microscopy image of dividing cells, with chromosomes in green. The chromosome in the middle is lagging, which can lead to incorrect chromosome number.

Beyond cell division

2 dividing cells are labeled in blue & red, with green chromosomes being split between the two cells
Microscopy image of dividing cancer cells, with chromosomes in green. The chromosome in the middle is lagging, which can lead to incorrect chromosome number.

The researchers also investigated the impact of aneuploidy on other biological pathways, such as transcription, the first stage of gene expression in which a segment of DNA is copied into RNA.

They found that here too, the effects of aneuploidy were varied across otherwise identical cells.

The cells’ response to environmental changes also varied considerably, suggesting that aneuploidy has an impact on the robustness of many, if not all, biological processes.

To ensure the response is not an effect that is unique to baker’s yeast cells, the researchers then studied the impact of aneuploidy on mice, and found the same levels of variability, Amon says.

“This suggests that the aneuploidy state itself could create variability, and that could provide an additional explanation of why diseases that are caused by aneuploidy are so variable,” Amon says.

Tumors, for example, are known to contain different populations of cells, some of which are quite different to each other in their genetic makeup. These genetic differences have often been blamed when chemotherapy or other treatments have been unsuccessful, as it was believed that the therapy may not have targeted all of the cells within the tumor.

“Unfortunately our paper suggests that tumors don’t even need to be heterogeneous genetically, the very fact that they have aneuploidy could lead to very variable outcomes, and that represents a significant challenge for cancer therapy,” Amon says.

Understanding the consequences of aneuploidy on cellular phenotypes is a fundamental question that has important implications for the treatment of several diseases, such as cancer and Down Syndrome, according to Giulia Rancati of the Institute of Medical Biology at the Agency for Science, Technology and Research (A*STAR) in Singapore, who was not involved in the research.

“This new exciting work adds an additional layer of understanding of how aneuploidy causes phenotypic variation, by revealing an unexpectedly high cell-to-cell variability between cells harboring the same aneuploidy karyotype,” Rancati says. “It would be interesting to test if this property of the aneuploid state might positively contribute to the evolution of cancer cells, which are known to develop drug resistance at high frequency.”

The researchers are now hoping to carry out further studies to investigate the origins of the variability, Amon says.

The results suggest that subtle changes in gene dosage across many genes, caused by the change in chromosome numbers, can promote alternate behaviors.

“We’re now trying to track down which the key genes are, and which the key pathways are,” she says. “Once we can understand what the key pathways are that cause this variability, we can start to think about targeting those pathways, to combat alternate outcomes in cancer treatment, for example.”

 

Helen Knight | MIT News correspondent

Mapping the brain at high resolution

New 3-D imaging technique can reveal, much more quickly than other methods, how neurons connect throughout the brain
Research Paper
A neuron and several other colorful brain structures
Neural structures imaged using a new high-resolution, nanoscale imaging system.

Researchers have developed a new way to image the brain with unprecedented resolution and speed. Using this approach, they can locate individual neurons, trace connections between them, and visualize organelles inside neurons, over large volumes of brain tissue.

The new technology combines a method for expanding brain tissue, making it possible to image at higher resolution, with a rapid 3-D microscopy technique known as lattice light-sheet microscopy. In a paper appearing in Science Jan. 17, the researchers showed that they could use these techniques to image the entire fruit fly brain, as well as large sections of the mouse brain, much faster than has previously been possible. The team includes researchers from MIT, the University of California at Berkeley, the Howard Hughes Medical Institute, and Harvard Medical School/Boston Children’s Hospital.

This technique allows researchers to map large-scale circuits within the brain while also offering unique insight into individual neurons’ functions, says Edward Boyden, the Y. Eva Tan Professor in Neurotechnology, an associate professor of biological engineering and of brain and cognitive sciences at MIT, and a member of the Alana Down Syndrome Center.

“A lot of problems in biology are multiscale,” Boyden says. “Using lattice light-sheet microscopy, along with the expansion microscopy process, we can now image at large scale without losing sight of the nanoscale configuration of biomolecules.”

Boyden is one of the study’s senior authors, along with Eric Betzig, a senior fellow at the Janelia Research Campus and a professor of physics and molecular and cell biology at UC Berkeley. The paper’s lead authors are MIT postdoc Ruixuan Gao, former MIT postdoc Shoh Asano, and Harvard Medical School Assistant Professor Srigokul Upadhyayula.

Large-scale imaging

In 2015, Boyden’s lab developed a way to generate very high-resolution images of brain tissue using an ordinary light microscope. Their technique relies on expanding tissue before imaging it, allowing them to image the tissue at a resolution of about 60 nanometers. Previously, this kind of imaging could be achieved only with very expensive high-resolution microscopes, known as super-resolution microscopes.

In the new study, Boyden teamed up with Betzig and his colleagues at HHMI’s Janelia Research Campus to combine expansion microscopy with lattice light-sheet microscopy. This technology, which Betzig developed several years ago, has some key traits that make it ideal to pair with expansion microscopy: It can image large samples rapidly, and it induces much less photodamage than other fluorescent microscopy techniques.

“The marrying of the lattice light-sheet microscope with expansion microscopy is essential to achieve the sensitivity, resolution, and scalability of the imaging that we’re doing,” Gao says.

Imaging expanded tissue samples generates huge amounts of data — up to tens of terabytes per sample — so the researchers also had to devise highly parallelized computational image-processing techniques that could break down the data into smaller chunks, analyze it, and stitch it back together into a coherent whole.

In the Science paper, the researchers demonstrated the power of their new technique by imaging layers of neurons in the somatosensory cortex of mice, after expanding the tissue volume fourfold. They focused on a type of neuron known as pyramidal cells, one of the most common excitatory neurons found in the nervous system. To locate synapses, or connections, between these neurons, they labeled proteins found in the presynaptic and postsynaptic regions of the cells. This also allowed them to compare the density of synapses in different parts of the cortex.

Yellow cells with cyan and magenta dots
Mouse neurons in yellow, with cyan and magenta markers for synapses, imaged with the new technique

MIT researchers have developed a method to perform large-scale, 3D imaging of brain tissue. Here, they image the entire fruit fly brain.

Using this technique, it is possible to analyze millions of synapses in just a few days.

“We counted clusters of postsynaptic markers across the cortex, and we saw differences in synaptic density in different layers of the cortex,” Gao says. “Using electron microscopy, this would have taken years to complete.”

The researchers also studied patterns of axon myelination in different neurons. Myelin is a fatty substance that insulates axons and whose disruption is a hallmark of multiple sclerosis. The researchers were able to compute the thickness of the myelin coating in different segments of axons, and they measured the gaps between stretches of myelin, which are important because they help conduct electrical signals. Previously, this kind of myelin tracing would have required months to years for human annotators to perform.

This technology can also be used to image tiny organelles inside neurons. In the new paper, the researchers identified mitochondria and lysosomes, and they also measured variations in the shapes of these organelles.

Circuit analysis

The researchers demonstrated that this technique could be used to analyze brain tissue from other organisms as well; they used it to image the entire brain of the fruit fly, which is the size of a poppy seed and contains about 100,000 neurons. In one set of experiments, they traced an olfactory circuit that extends across several brain regions, imaged all dopaminergic neurons, and counted all synapses across the brain. By comparing multiple animals, they also found differences in the numbers and arrangements of synaptic boutons within each animal’s olfactory circuit.

In future work, Boyden envisions that this technique could be used to trace circuits that control memory formation and recall, to study how sensory input leads to a specific behavior, or to analyze how emotions are coupled to decision-making.

“These are all questions at a scale that you can’t answer with classical technologies,” he says.

The system could also have applications beyond neuroscience, Boyden says. His lab is planning to work with other researchers to study how HIV evades the immune system, and the technology could also be adapted to study how cancer cells interact with surrounding cells, including immune cells.

The research was funded by K. Lisa Yang and Y. Eva Tan, John Doerr, the Open Philanthropy Project, the National Institutes of Health, the Howard Hughes Medical Institute, the HHMI-Simons Faculty Scholars Program, the U.S. Army Research Laboratory and Army Research Office, the US-Israel Binational Science Foundation, Biogen, and Ionis Pharmaceuticals.

Anne Trafton, MIT News Office

Brain Wave Stimulation May Improve Alzheimer’s Symptoms

A combination of light and sound can improve hallmarks of Alzheimer's in mice
Research Paper
Microscope image of a light & sound treated mouse brain, cells labeled in blue, amyloid plaques in red.
Microscope image of a light & sound treated mouse brain, cells labeled in blue, amyloid plaques in red.

By exposing mice to a unique combination of light and sound, MIT neuroscientists have shown that they can improve cognitive and memory impairments similar to those seen in Alzheimer’s patients. Individuals with Down syndrome have a high risk of developing Alzheimer’s Disease.

This noninvasive treatment, which works by inducing brain waves known as gamma oscillations, also greatly reduced the number of amyloid plaques found in the brains of these mice. Plaques were cleared in large swaths of the brain, including areas critical for cognitive functions such as learning and memory.

“When we combine visual and auditory stimulation for a week, we see the engagement of the prefrontal cortex and a very dramatic reduction of amyloid,” says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the Alana Down Syndrome Center, and the senior author of the study.

Further study will be needed, she says, to determine if this type of treatment will work in human patients. The researchers have already performed some preliminary safety tests of this type of stimulation in healthy human subjects.

MIT graduate student Anthony Martorell and Georgia Tech graduate student Abigail Paulson are the lead authors of the study, done in collaboration with Alana Investigator Ed Boyden’s lab, which appears in the March 14 issue of Cell.

Memory improvement

The brain’s neurons generate electrical signals that synchronize to form brain waves in several different frequency ranges. Previous studies have suggested that Alzheimer’s patients have impairments of their gamma-frequency oscillations, which range from 25 to 80 hertz (cycles per second) and are believed to contribute to brain functions such as attention, perception, and memory.

In 2016, Tsai and her colleagues first reported the beneficial effects of restoring gamma oscillations in the brains of mice that are genetically predisposed to develop Alzheimer’s symptoms. In that study, the researchers used light flickering at 40 hertz, delivered for one hour a day. They found that this treatment reduced levels of beta amyloid plaques and another Alzheimer’s-related pathogenic marker, phosphorylated tau protein. The treatment also stimulated the activity of debris-clearing immune cells known as microglia.

In that study, the improvements generated by flickering light were limited to the visual cortex. In their new study, the researchers set out to explore whether they could reach other brain regions, such as those needed for learning and memory, using sound stimuli. They found that exposure to one hour of 40-hertz tones per day, for seven days, dramatically reduced the amount of beta amyloid in the auditory cortex (which processes sound) as well as the hippocampus, a key memory site that is located near the auditory cortex.

“What we have demonstrated here is that we can use a totally different sensory modality to induce gamma oscillations in the brain. And secondly, this auditory-stimulation-induced gamma can reduce amyloid and Tau pathology in not just the sensory cortex but also in the hippocampus,” says Tsai, a founding member of MIT’s Aging Brain Initiative.

The researchers also tested the effect of auditory stimulation on the mice’s cognitive abilities. They found that after one week of treatment, the mice performed much better when navigating a maze requiring them to remember key landmarks. They were also better able to recognize objects they had previously encountered.

They also found that auditory treatment induced changes in not only microglia, but also the blood vessels, possibly facilitating the clearance of amyloid.

Dramatic effect

Brain cells called microglia, labeled green, change shape after light treatment

The researchers then decided to try combining the visual and auditory stimulation, and to their surprise, they found that this dual treatment had an even greater effect than either one alone. 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.

“These microglia just pile on top of one another around the plaques,” Tsai says. “It’s very dramatic.”

The researchers found that if they treated the mice for one week, then waited another week to perform the tests, many of the positive effects had faded, suggesting that the treatment would need to be given continually to maintain the benefits.

In an ongoing study, the researchers are now analyzing how gamma oscillations affect specific brain cell types, in hopes of discovering the molecular mechanisms behind the phenomena they have observed. Tsai says she also hopes to explore why the specific frequency they use, 40 hertz, has such a profound impact.

The combined visual and auditory treatment has already been tested in healthy volunteers, to assess its safety, and the researchers are now beginning to enroll patients with early-stage Alzheimer’s to study its possible effects on the disease.

“Though there are important differences among species, there is reason to be optimistic that these methods can provide useful interventions for humans,” says Nancy Kopell, a professor of mathematics and statistics at Boston University, who was not involved in the research. “This paper and related studies have the potential for huge clinical impact in Alzheimer’s disease and others involving brain inflammation.”

Anne Trafton, MIT News