Category: Li-Hue Tsai

Li-Huei Tsai is shown in profile as she stands smiling at a podium

Li-Huei Tsai elected to American Academy of Arts & Sciences

The American Academy of Arts & Sciences announced today that Li-Huei Tsai, Picower Professor of Neuroscience and Director of The Picower Institute for Learning & Memory, is among 252 luminaries elected to join its esteemed membership.

“We are honoring the excellence of these individuals, celebrating what they have achieved so far, and imagining what they will continue to accomplish,” said David Oxtoby, President of the American Academy, in the announcement. “The past year has been replete with evidence of how things can get worse; this is an opportunity to illuminate the importance of art, ideas, knowledge, and leadership that can make a better world.”

Tsai’s laboratory focuses on advancing understanding the molecular-, circuit- and systems-level mechanisms underlying neurodegenerative diseases such as Alzheimer’s. She has translated many of her lab’s fundamental insights into potential therapeutic approaches.

“I’m very honored to be elected to the academy and to be in the company of so many leading scholars and luminaries,” Tsai said. “The Academy’s mission of advancing the public good is also a philosophy that guides our work to understand and address neurodegenerative diseases such as Alzheimer’s disease. This recognition encourages us to continue our efforts with urgency and rigor.”

With her election, Tsai joins other Picower Institute faculty in the academy including Mark Bear, Emery N. Brown, Earl Miller, Mriganka Sur, Susumu Tonegawa and Matt Wilson. Also this year, four other MIT faculty members were elected to membership.

Study offers an explanation for why the APOE4 gene enhances Alzheimer’s risk

Gene variant disrupts lipid metabolism, but in experiments the effects were reversed by choline supplements

One of the most significant genetic risk factors for developing Alzheimer’s disease is a gene called APOE4, which is carried by almost half of all Alzheimer’s patients. A new study from MIT shows that this gene has widespread effects on brain cells’ ability to metabolize lipids and respond to stress.

In studies of human brain cells and yeast cells, the researchers found that the APOE4 gene significantly disrupts brain cells’ ability to carry out their normal functions. They also showed that treating these cells with extra choline, a widely available supplement that is considered safe for human use, could reverse many of these effects.

The researchers hope that their findings will lead to clinical studies of choline in people who carry the APOE4 gene, who make up about 14 percent of the overall population. Previous trials looking at choline’s effects on cognition showed mixed results, but those trials were not targeted specifically to people with the APOE4 gene.

“What we would really like to see is whether in the human population, in those APOE4 carriers, if they take choline supplements to a sufficient amount, whether that would delay or give them some protection against developing dementia or Alzheimer’s disease,” says Li-Huei Tsai, the director of MIT’s Picower Institute for Learning and Memory.

Tsai and the late Susan Lindquist, former director of MIT’s Whitehead Institute for Biomedical Research, are the senior authors of the study, which appears today in Science Translational Medicine. The paper’s three lead authors are former Whitehead and MIT postdocs Grzegorz Sienski and Priyanka Narayan, and current MIT postdoc Julia Maeve Bonner.

Lipid dysregulation

The human gene for APOE, or apolipoprotein E, comes in three versions. While APOE4 is linked to higher risk for Alzheimer’s, APOE2 is considered protective, and APOE3, the most common variant, is neutral.

APOE is known to be involved in lipid metabolism, but its role in the development of Alzheimer’s has been unclear, Tsai says. To try to learn more about this connection, the researchers created human induced pluripotent stem cells that carry either the APOE3 or APOE4 gene in an otherwise identical genetic background. They then stimulated these cells to differentiate into astrocytes, the brain cells that produce the most APOE.

APOE4 astrocytes showed dramatic changes in how they process lipids compared to APOE3. In APOE4 astrocytes, there was a significant buildup of neutral lipids and cholesterol. These astrocytes also accumulated droplets containing a type of lipids called triglycerides, and these triglycerides had many more unsaturated fatty acid chains than normal. These changes all disrupt the normal lipid balance inside the cells. The authors also noted APOE4-dependent lipid disruptions in another important brain cell, microglia.

“When lipid homeostasis is compromised, then a lot of very essential processes are affected, such as intracellular trafficking, vesicular trafficking, and endocytosis. A lot of the cells’ essential functions are compromised,” Tsai says.

“This balance is really important for cells to be able to perform normal functions like generate membranes and so on, but also to be able to absorb stress,” Bonner says. “We think that one of the things that’s happening is that these cells are less able to absorb stress because they’re already in this heightened lipid dysregulation state.”

The researchers also found that yeast cells engineered to express the human version of APOE4 showed many of the same defects. Using these cells, they performed a systematic genetic screen to determine the molecular basis of the defects seen in APOE4 cells. This screen showed that turning on a pathway that normally produces phospholipids, an essential component of cell membranes, can reverse some of the damage seen in APOE4 cells. This suggests that APOE4 somehow increases the requirement for phospholipid synthesis.

The researchers also found that growing APOE4 yeast cells on a very nutrient-rich growth medium helped them to survive better than APOE4 yeast cells grown on the typical growth medium. Further experiments revealed that the nutrient that helped APOE4 cells survive is choline, a building block that cells use to make phospholipids. The researchers then treated their human APOE4 astrocyte cells with choline to promote phospholipid synthesis, and found that it also reversed much of the damage they had seen in those cells, including the accumulation of cholesterol and lipid droplets.

Choline deficiency

The researchers have now begun studying a mouse model of Alzheimer’s that is also engineered to express the human APOE4 gene. They hope to investigate whether choline can help to reverse some of the symptoms of Alzheimer’s in these mice.

Choline is naturally found in foods such as eggs, meat, fish, and some beans and nuts. The minimum recommended intake of choline is 550 milligrams per day for men and 425 milligrams per day for women, but most people don’t consume that much, Tsai says. The new study offers preliminary evidence that people who carry the APOE4 gene may benefit from taking choline supplements, she says, although clinical trials are necessary to confirm that.

“What our results suggest is that if you are an APOE2 or APOE3 carrier, even you are somewhat choline deficient you can cope with it,” Tsai says. “But if you are an APOE4 carrier, then if you don’t take enough choline, then that will have a more dire consequences. The APOE4 carriers are more susceptible to choline deficiency.”

The research was funded by the EMBO Fellowship, the Helen Hay Whitney Foundation, the National Institutes of Health, the Damon Runyon Foundation, the Neurodegeneration Consortium, the Robert A. and Renee E. Belfer Foundation, the Howard Hughes Medical Institute, the Ludwig Family Foundation, and Kara and Stephen Ross.

–From MIT News

Long, thin,spiny cells stained yellow and blue appear above a black background

Alzheimer’s risk gene disrupts endocytosis, but another disease-linked gene could help

In a new study, a team of scientists based at The Picower Institute for Learning and Memory at MIT and the Whitehead Institute for Biomedical Research reveals evidence showing that the most prominent Alzheimer’s disease risk gene may disrupt a fundamental process in a key type of brain cell. Moreover, in a sign of how important it is to delve into the complex ways that genes intersect in disease, they found that increasing the expression of another Alzheimer’s-associated gene in those cells could help alleviate the problem.

About 25 percent of people have the APOE4 variant of the APOE gene, which puts them at substantially greater risk for Alzheimer’s disease than those with the more common APOE3 version. Scientists have been working for decades to understand why this is so. The new study in Cell Reports finds that in astrocytes, which are the most common non-neuron cell in the brain, the variant hampers the process of endocytosis, which is a major way that cells bring materials in from outside. That functional deficit could undermine several of the vital roles that astrocytes play in the brain, the researchers noted, including how they facilitate communication among neurons or maintain the blood-brain barrier, which stringently filters what circulates into or out of the brain.

“We have identified that APOE4 imposes an endocytosis deficiency in astrocytes,” said Priyanka Narayan, a researcher at the National Institutes of Health who co-led the work while a postdoc in the labs of the late Susan Lindquist, member of the Whitehead Institute, and of Li-Huei Tsai, Picower Professor of Neuroscience and the study’s corresponding author. “This effect could have a number of downstream consequences such as impaired communication with other cell types, poor clearance of extracellular material, or poor maintenance of metabolic homeostasis.”


Above: Astrocytes, such as these cells derived from induced pluripotent stem cells, are critical for brain function.


The research began in the lab of Lindquist, who was also a Professor of Biology at MIT. Lindquist and Tsai, were close collaborators. After Lindquist died, the research team completed the work in the Tsai lab at MIT. The study’s co-lead author is Grzegorz Sienski of the Whitehead Institute.

As part of their work, the team also found that in APOE4-carrying astrocytes increasing expression of an Alzheimer’s associated gene called PICALM reversed the endocytosis defects.

“Both APOE and PICALM are Alzheimer’s risk genes,” said Tsai, a founding director of MIT’s Aging Brain Initiative. “It is really interesting that the two genes converge on endocytosis. This indicates that faulty endocytosis plays a key role in the etiology of Alzheimer’s.”

Reduction and rescue

For at least a decade, studies have suggested connections among Alzheimer’s, APOE4 and errant endocytosis, but have not pinpointed specific mechanisms. The team sought them out—and also looked for ways to remediate the deficits—through a series of lab experiments in cultures of stem cell-derived human astrocytes and genetically engineered yeast. Tsai’s team focused on astrocytes because they produce the most ApoE protein in the brain.

By comparing astrocytes that were identical except in whether they had the APOE4 or APOE3 variants, the researchers found several signs of disrupted endocytosis, specifically in the early stage of the process when key proteins were notably reduced in the APOE4 carrying cells. They were able to directly observe that the afflicted astrocytes were less capable of bringing in materials from the outside. When they knocked out the APOE gene they no longer saw a defect in early endocytosis, affirming that the problem related to having the APOE4 variant.

By engineering human APOE3 and APOE4 into yeast cells, Tsai’s team was able to replicate clear signs of APOE4’s early endocytic disruption. This is possible because the function is so fundamental to how cells work, it is similar, or “conserved,” in yeast and people.  Once they knew they could use yeast as a model, they could then set out to look for endocytosis proteins that, if manipulated, could rescue the observed defect. They found one: a yeast protein called Yap1802p. When they made the yeast cells express extra Yap1802p, early endocytosis proteins were produced at normal levels, endocytosis function operated better and APOE4 cells, which had failed to grow as healthfully as APOE3 cells did, exhibited better growth.

Importantly, the gene that encodes Yap1802p has a human counterpart: PICALM. Studies have shown PICALM to have a complex but significant role in affecting Alzheimer’s disease risk.

A 3 by 2 grid shows cells with blue and white staining
In the bottom row, APOE4 astrocytes (blue) in which PICALM was overexpressed show greater uptake of transferrin protein (white) than APOE4 astrocytes without PICALM overexpression (top row).

With their promising results in yeast, the researcher team returned to their human astrocyte cultures. Overexpressing PICALM in APOE4 astrocytes repaired early endocytosis function, as measured by the increased intake of test proteins. But they also saw that overexpressing PICALM in APOE3 astrocytes caused an endocytosis defect, illustrating that the effects of PICALM varies markedly in astrocytes based on APOE variant.

Although, it is difficult to find drugs that specifically increase endocytosis,  this study could help scientists and clinicians better understand patients’ risk, Narayan said.

“In our study, we see that in the context of an APOE4 genotype, increasing PICALM can alleviate deficiencies in early endocytosis,” she said. “Given that APOE4 carriers represent a significant proportion of AD patients, this functional interaction between APOE4 and PICALM could be relevant to assessing their level of disease risk. It also gives an example of how the genetic background of an individual can interact and potentially modulate the detrimental effects of the APOE4 genotype.”

Moreover, the team’s method of going back and forth between human cell cultures and yeast, provides a way of identifying how AD risk genes impact cellular biology, and how other genes can modulate these effects.

In addition to Narayan, Sienski and Tsai, the study’s other authors are Julia Maeve Bonner, Yuan-Ta Lin, Jinsoo Seo, Valeriya Baru, Aftabul Haque, Blerta Milo, Leyla Akay, Agnese Graziosi, Yelena Freyzon, Dirk Landgraf, William Hesse, Julie Valastyan, M. Inmaculada Barrasa and the late Susan Lindquist, a former Professor of Biology at MIT and The Whitehead Institute.

The National Institutes of Health, the Whitehead Institute, the Robert A. and Renee E. Belfer Family Foundation, the JPB Foundation, the Edward N. and Della L. Thome Foundation and the Howard Hughes Medical Institute funded the research.

Li-Huei Tsai smiles in a picture with a video play button superposed in the foreground

On The Same Wavelength

In a new video, MIT’s School of Science provides an inside look behind the Tsai lab’s discovery that stimulating 40Hz “gamma” frequency brain activity in mice can address Alzheimer’s pathology and symptoms, including memory loss and neuronal death.  Part of the “Moments of Discovery” series, the video recreates former graduate student Hannah Iaccarino’s key early experiments.

Rainbow hued blood vessels spread out in a weblike formation

Study finds path for addressing Alzheimer’s blood-brain barrier impairment

By developing a lab-engineered model of the human blood-brain barrier (BBB), neuroscientists at MIT’s Picower Institute for Learning and Memory 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.

A grayish loop of blood vessel on a black background is covered with green blotches
A 3D rendering of an APOE4 carrying engineered blood vessel shows heavy accumulation of amyloid protein (green).

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 Professor of Neuroscience and director of the Picower Institute. 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, a founding member of MIT’s Aging Brain Initiative. “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.

A six panel grid showing neurons stained in red or green

Study finds that aging neurons accumulate DNA damage

MIT neuroscientists have discovered that an enzyme called HDAC1 is critical for repairing age-related DNA damage to genes involved in memory and other cognitive functions. This enzyme is often diminished in both Alzheimer’s patients and normally aging adults. In a study of mice, the researchers showed that when HDAC1 is lost, a specific type of DNA damage builds up as the mice age. They also showed that they could reverse this damage and improve cognitive function with a drug that activates HDAC1.

The study suggests that restoring HDAC1 could have positive benefits for both Alzheimer’s patients and people who suffer from age-related cognitive decline, the researchers say.

“It seems that HDAC1 is really an anti-aging molecule,” says Li-Huei Tsai, the director of MIT’s Picower Institute for Learning and Memory and the senior author of the study. “I think this is a very broadly applicable basic biology finding, because nearly all of the human neurodegenerative diseases only happen during aging. I would speculate that activating HDAC1 is beneficial in many conditions.”

Picower Institute research scientist Ping-Chieh Pao is the lead author of the study, which appears today in Nature Communications.

DNA repair and aging

There are several members of the HDAC family of enzymes, and their primary function is to modify histones — proteins around which DNA is spooled. These modifications control gene expression by blocking genes in certain stretches of DNA from being copied into RNA.

In 2013, Tsai’s lab published two papers that linked HDAC1 to DNA repair in neurons. In the current paper, the researchers explored what happens when HDAC1-mediated repair fails to occur. To do that, they engineered mice in which they could knock out HDAC1 specifically in neurons and another type of brain cells called astrocytes.

For the first several months of the mice’s lives, there were no discernable differences in their DNA damage levels or behavior, compared to normal mice. However, as the mice aged, differences became more apparent. DNA damage began to accumulate in the HDAC1-deficient mice, and they also lost some of their ability to modulate synaptic plasticity — changes in the strength of the connections between neurons. The older mice lacking HCAC1 also showed impairments in tests of memory and spatial navigation.

The researchers found that HDAC1 loss led to a specific type of DNA damage called 8-oxo-guanine lesions, which are a signature of oxidative DNA damage. Studies of Alzheimer’s patients have also shown high levels of this type of DNA damage, which is often caused by accumulation of harmful metabolic byproducts. The brain’s ability to clear these byproducts often diminishes with age.

An enzyme called OGG1 is responsible for repairing this type of oxidative DNA damage, and the researchers found that HDAC1 is needed to activate OGG1. When HDAC1 is missing, OGG1 fails to turn on and DNA damage goes unrepaired. Many of the genes that the researchers found to be most susceptible to this type of damage encode ion channels, which are critical for the function of synapses.

Targeting neurodegeneration

Several years ago, Tsai and Stephen Haggarty of Harvard Medical School, who is also an author of the new study, screened libraries of small molecules in search of potential drug compounds that activate or inhibit members of the HDAC family. In the new paper, Tsai and Pao used one of these drugs, called exifone, to see if they could reverse the age-related DNA damage they saw in mice lacking HDAC1.

The researchers used exifone to treat two different mouse models of Alzheimer’s, as well as healthy older mice. In all cases, they found that the drug reduced the levels of oxidative DNA damage in the brain and improved the mice’s cognitive functions, including memory.

Exifone was approved in the 1980s in Europe to treat dementia but was later taken off the market because it caused liver damage in some patients. Tsai says she is optimistic that other, safer HDAC1-activating drugs could be worth pursuing as potential treatments for both age-related cognitive decline and Alzheimer’s disease.

“This study really positions HDAC1 as a potential new drug target for age-related phenotypes, as well as neurodegeneration-associated pathology and phenotypes,” she says.

Tsai’s lab is now exploring whether DNA damage and HDAC1 also play a role in the formation of Tau tangles — misfolded proteins in the brain that are a signature of Alzheimer’s and other neurodegenerative diseases.

The research was funded by the National Institute on Aging, the National Institute of Neurological Disorders and Stroke, and a Glenn Award for Research in Biological Mechanisms of Aging.

–From MIT News

In mouse brains stained for the presence of amyloid, much less is visible in the cortex of a mouse treated with sensory gamma stimulation (right) than in a mouse left untreated (left).

In Cell: Brain wave stimulation may improve Alzheimer’s symptoms

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.

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 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, which appears in the March 14 issue of Cell.

Continue reading…

Review: DNA Damage and Its Links to Neurodegeneration

The integrity of our genetic material is under constant attack from numerous endogenous and exogenous agents. The consequences of a defective DNA damage response are well studied in proliferating cells, especially with regards to the development of cancer, yet its precise roles in the nervous system are relatively poorly understood. Here we attempt to provide a comprehensive overview of the consequences of genomic instability in the nervous system. We highlight the neuropathology of congenital syndromes that result from mutations in DNA repair factors and underscore the importance of the DNA damage response in neural development. In addition, we describe the findings of recent studies, which reveal that a robust DNA damage response is also intimately connected to aging and the manifestation of age-related neurodegenerative disorders such as Alzheimer’s disease and amyotrophic lateral sclerosis.

Video Abstract

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Neuroscientists find that limiting a certain protein in the brain reverses Alzheimer’s symptoms in mice

Limiting a certain protein in the brain reverses Alzheimer’s symptoms in mice, report neuroscientists at MIT’s Picower Intitute for Learning and Memory.

Researchers found that the overproduction of the protein known as p25 may be the culprit behind the sticky protein-fragment clusters that build up in the brains of Alzheimer’s patients. The work, which was published in the April 10 issue of Cell, could provide a new drug target for the treatment of the disease that affects more than five million Americans, says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and senior author of the paper.

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Drug Tweaks Epigenome to Erase Fear Memories

A hurricane, a car accident, a roadside bomb, a rape — extreme stress is more common than you might think, with an estimated 50 to 60 percent of Americans experiencing it at some point in their lives. About 8 percent of that group will be diagnosed with post-traumatic stress disorder, or PTSD. They will have flashbacks and nightmares. They will feel amped up, with nerves on a permanent state of high alert. They won’t be able to forget.

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Li-Huei Tsai

Science In Mind

MIT researchers find a drug that helps erase traumatic memories in mice.

For years, neuroscientist Li-Huei Tsai has been unraveling the brain circuits that underlie memory, searching for approaches that might be helpful in treating Alzheimer’s disease. In 2007, the Massachusetts Institute of Technology scientist identified an experimental drug that could restore lost memories in mice. Lately, she has been wondering whether that kind of drug might be useful to help people forget traumatic events that cause fear and anxiety.

In a study published Thursday in the journal Cell, Tsai and colleagues used a single dose of the drug, called an HDAC inhibitor, to help mice extinguish a fearful memory of a traumatic event that took place in the distant past.

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By Carolyn Y. Johnson / Globe Staff

Erasing Traumatic Memories

Erasing traumatic memories

New study identifies drug that could improve treatment of posttraumatic stress disorder.

Nearly 8 million Americans suffer from posttraumatic stress disorder (PTSD), a condition marked by severe anxiety stemming from a traumatic event such as a battle or violent attack.

Many patients undergo psychotherapy designed to help them re-experience their traumatic memory in a safe environment so as to help them make sense of the events and overcome their fear. However, such memories can be so entrenched that this therapy doesn’t always work, especially when the traumatic event occurred many years earlier.

MIT neuroscientists have now shown that they can extinguish well-established traumatic memories in mice by giving them a type of drug called an HDAC2 inhibitor, which makes the brain’s memories more malleable, under the right conditions. Giving this type of drug to human patients receiving psychotherapy may be much more effective than psychotherapy alone, says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory.

Illustration: Christine Daniloff/MIT

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DNA damage may cause ALS

New study finds link between neurons’ inability to repair DNA and neurodegeneration.

Amyotrophic lateral sclerosis (ALS) — also known as Lou Gehrig’s disease — is a neurodegenerative disease that destroys the neurons that control muscle movement. There is no cure for ALS, which kills most patients within three to five years of the onset of symptoms, and about 5,600 new cases are diagnosed in the United States each year.

MIT neuroscientists have found new evidence that suggests that a failure to repair damaged DNA could underlie not only ALS, but also other neurodegenerative disorders such as Alzheimer’s disease. These findings imply that drugs that bolster neurons’ DNA-repair capacity could help ALS patients, says Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and senior author of a paper describing the ALS findings in the Sept. 15 issue of Nature Neuroscience.

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Histone acetylation: molecular mnemonics on the chromatin

Long-lasting memories require specific gene expression programmes that are, in part, orchestrated by epigenetic mechanisms. Of the epigenetic modifications identified in cognitive processes, histone acetylation has spurred considerable interest. Whereas increments in histone acetylation have consistently been shown to favour learning and memory, a lack thereof has been causally implicated in cognitive impairments in neurodevelopmental disorders, neurodegeneration and ageing. As histone acetylation and cognitive functions can be pharmacologically restored by histone deacetylase inhibitors, this epigenetic modification might constitute a molecular memory aid on the chromatin and, by extension, a new template for therapeutic interventions against cognitive frailty.

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Li-Huei Tsai

Li-Huei Tsai: I well remember

Tsai studies how Cdk5 activity affects brain development, learning, and memory.

Cdk5 is a kinase expressed mainly in neurons, where it helps regulate the activity of a whole host of downstream targets, including ion channels and synaptic scaffold proteins. Thus, it’s perhaps to be expected that Cdk5 dysregulation is associated with many neuropathologies.

Li-Huei Tsai cloned Cdk5 as a postdoc and decided she wanted to study it further in her own lab. When asked during job interviews what she would do if Cdk5 wasn’t involved in any interesting phenotypes, she replied that she would no doubt find something else interesting to study. She was soon hired on at Harvard. As it turns out, though, Cdk5 (and its regulation) is plenty interesting, as we learned when we called her at her current lab at the Massachusetts Institute of Technology.

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Re-opening the Memory Book

Following the completion of the Human Genome Project, much of biology’s focus has been shifted from the raw sequence of genes to their regulation over time and in response to environmental stimuli. Like books on a shelf, genes do not exert effects by their mere presence; rather, the pages of the book (i.e., the chromatin) need to be opened so that the words (i.e., the genes) can be read and interpreted correctly. The epigenetic regulation of gene expression refers precisely to this process.

In 1984, Francis Crick (1916-2004) proposed that memory might be coded in alterations to particular stretches of chromosomal DNA. Although the response to this idea was relatively modest at the time, the past decade has shown that chromatin, the carrier of chromosomal DNA, undergoes dynamic modifications and conformational changes during memory formation. One of these modifications is histone acetylation, the addition of an acetyl group to histone proteins. Histone acetylation is regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs) and generally closely correlates with active gene expression. Rodents display a transient increase in histone acetylation after exposure to various learning paradigms, and synaptic plasticity and memory formation are facilitated after treatment with small molecule inhibitors of HDACs.

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Reversing Alzheimer’s gene ‘blockade’ can restore memory, other cognitive functions

Neuroscientists show that HDAC2 enzyme could be a good target for new drugs.

MIT neuroscientists have shown that an enzyme overproduced in the brains of Alzheimer’s patients creates a blockade that shuts off genes necessary to form new memories. Furthermore, by inhibiting that enzyme in mice, the researchers were able to reverse Alzheimer’s symptoms.

The finding suggests that drugs targeting the enzyme, known as HDAC2, could be a promising new approach to treating the disease, which affects 5.4 million Americans. The number of Alzheimer’s victims worldwide is expected to double every 20 years, and President Barack Obama recently set a target date of 2025 to find an effective treatment.

Li-Huei Tsai, leader of the research team, says that HDAC2 inhibitors could help achieve that goal, though it would likely take at least 10 years to develop and test such drugs.

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Unraveling how a mutation can lead to psychiatric illness

MIT neuroscientists show that a gene linked with schizophrenia and bipolar disorder impairs early brain development.

In recent years, scientists have discovered several genetic mutations associated with greater risk of psychiatric diseases such as schizophrenia and bipolar disorder. One such mutation, known as DISC1 — an abbreviation for “Disrupted in Schizophrenia-1” — was first identified in a large Scottish family with high rates of schizophrenia, bipolar disorder and depression.

Studies have since shown that DISC1 mutations can lead to altered brain structure and impaired cognition, but it was unknown exactly how this occurs. A new study from Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory, shows that DISC1 mutations impair a specific signaling pathway in neurons that is critical for normal brain development.

In a genetic screen of 750 people — some of whom were healthy and some of whom had psychiatric diseases — the researchers found several common variants of the DISC1 gene. However, even though these mutations disrupted normal brain development, they were not necessarily enough to cause disease on their own.

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