neurodegenerative diseases Archives - Sanford Burnham Prebys

Tag: neurodegenerative diseases

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Using stem cells to study the biochemistry of learning

AuthorMiles Martin
Date

August 18, 2022

Neural networks grown from human stem cells

A method for studying human neurons could help researchers develop approaches for treating Alzheimer’s, schizophrenia and other neurological diseases

Researchers from the Conrad Prebys Center for Chemical Genomics have developed a procedure to use neurons derived from human stem cells to study the biological processes that control learning and memory. The method, described in Stem Cell Reports, uses electrodes to measure the activity of neuronal networks grown from human-induced pluripotent stem cells (iPSCs). The procedure tracks how synapses—the connections between neurons—strengthen over time, a process called long-term potentiation (LTP).

“Impaired long-term potentiation is thought to be central to many neurological diseases, including Alzheimer’s, addiction and schizophrenia,” says senior author Anne Bang, PhD, director of Cell Biology at the Prebys Center. “We’ve developed an approach to study this process in human cells much more efficiently than current methods, which could help trigger future breakthroughs for researchers working on these diseases.”

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

LTP helps our brain encode information, which is what makes it so critical for learning and memory. Impairment of LTP is thought to contribute to neurological diseases, but it has proven difficult to verify this hypothesis in human cells.

Anne Bang, PhD, director of Cell Biology at the Prebys Center.

“LTP is such a fundamental process,” says Bang. “But the human brain is hard to study directly because it’s so inaccessible. Using neurons derived from human stem cells helps us work around that.”

Although LTP can be studied in animals, these studies can’t easily account for some of the more human nuances of neurological diseases.

“A powerful aspect of human stem cell technology is that it allows us to study neurons produced from patient stem cells. Using human cells with human genetics is important in these types of tests because many neurological diseases have complex genetics underpinning them, and it’s rarely just one or two genes that influence a disease,” adds Bang.

To develop the method, first author and Prebys Center staff scientist Deborah Pré, PhD, grew networks of neurons from healthy human stem cells, added chemicals known to initiate LTP and then used electrodes to monitor changes in neuronal activity that occurred throughout the process.

The method can run 48 tests at once, and neurons continue to exhibit LTP up to 72 hours after the start of the experiment. These are distinct advantages over other approaches, which can often only observe parts of the process and are low throughput, which can make getting results more time consuming.

For this study, the researchers used neurons grown from healthy stem cells to establish a baseline understanding of LTP. The next step is to use the approach on neurons derived from patient-derived stem cells and compare these results to the baseline to see how neurological diseases influence the LTP process.

“This is an efficient method for interrogating human stem cell–derived neurons,” says Bang. “Doing these tests with patient cells could open doors for researchers to discover new ways of treating neurological diseases.”

Institute News

New insights into Alzheimer’s disease

AuthorMonica May
Date

September 25, 2020

Long neurites growing from neurons with extra SORLA

Sanford Burnham Prebys scientist publishes two papers that bring us one step closer to understanding—and potentially treating—the devastating condition.

For millions of families and caregivers around the world, the need for an effective treatment for Alzheimer’s disease remains urgent despite the ongoing pandemic. Now, two studies from Timothy Huang, PhD, who was recently promoted to assistant professor in the Degenerative Diseases Program at Sanford Burnham Prebys, bring us one step closer to understanding the root cause of the disease.

Brain protein may help protect against Alzheimer’s disease  

Previous research from Huang and his colleagues showed that a neuronal protein called SORLA helps reduce production of toxic amyloid beta protein that accumulates and leads to Alzheimer’s disease. Given this important role, Huang decided to dig deeper to understand SORLA’s “job” inside the brain.

In a paper featured on the cover of The Journal of Neuroscience, Huang and his team analyzed mice that produce high levels of SORLA and studied the effects of enhancing SORLA on the brain. This work showed that higher levels of SORLA resulted in elongated neurites, structures that extend from neurons, and improved the repair and regeneration of axons—the cable-like fibers that neurons use to communicate. These findings suggest that drugs that increase levels of SORLA might help protect the brain against Alzheimer’s disease and may even help people with a spinal cord injury. 

Huang describes the findings as “the tip of the iceberg” and is eager to learn more about this important protein—with the ultimate goal of identifying potential targets for drugs that could slow the progression of Alzheimer’s disease. 

A new model for studying Alzheimer’s disease 

Many of the mutations associated with Alzheimer’s disease are found in a brain cell type called microglia. However, unlike other cells, mouse microglia are very different from human microglia. Because scientists primarily use mouse models to understand disease, this difference limits their ability to understand how microglial mutations lead to Alzheimer’s disease.  

To overcome this hurdle, Huang and his team took on the formidable task of creating human stem cell lines that contain Alzheimer’s mutations found in human microglia. The scientists then tracked the downstream effects of these mutations in the cells, including epigenetic and gene expression changes, which revealed many new, previously unknown relationships between Alzheimer’s-associated genes. The findings were published in the Journal of Experimental Medicine. 

More studies are needed to fully understand the how these interactions alter the course of Alzheimer’s disease—which can now be answered using this new model. Huang, who describes the work as “one of the most challenging and ambitious projects I’ve worked on so far” believes the cell line may also be used to help screen for potential Alzheimer’s disease drugs. 
 

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Rett Syndrome Foundation funds a potential cure

AuthorSusan Gammon
Date

April 23, 2020

Crystal Zhao profile photo

The research may lead to a major step toward a cure.

Rett syndrome is a neurodevelopmental disorder that affects almost all aspects of a child’s life, from walking to eating to intellectual capability. There is no cure for the disease, which occurs mostly in girls, and treatments are aimed at slowing the loss of abilities and alleviating the debilitating symptoms. 

Jing Crystal Zhao, PhD, associate professor at Sanford Burnham Prebys, has received new funding from the Rett Syndrome Foundation to find ways to reverse the changes in a gene that causes Rett syndrome. The research may lead to a major step toward a cure.

“I’m very grateful to the Rett Syndrome Foundation, and excited to begin this project,” says Zhao. “While Rett syndrome may not be well known among the general public, our research may lead to treatments to improve the lives of patients around the world.”

More than 90% of Rett Syndrome cases are caused by genetic changes in a gene called MECP2. Every female carries two copies of the MECP2 gene. Rett syndrome patients carry both a normal and a mutant copy of MECP2. Unfortunately, in some cells, the normal copy of MEPC2 becomes inactive due to a biological process called X-chromosome inactivation—a process that occurs in females—and this leads to Rett syndrome. 

“Recent studies suggest that reversing X-chromosome inactivation could reactivate the normal copy of the MECP2 gene,” says Zhao. “We have identified an DNA element that plays a key role in X-chromosome inactivation. We are now going to test if we can block this element and restore the silent MECP2 gene, which could be life changing. 

“Our aim is to help individuals regain the skills and abilities stolen by Rett syndrome,” adds Zhao. “This award takes us closer to that goal.” 
 

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Top neuroscientists gather at Sanford Burnham Prebys’ annual symposium

AuthorMonica May
Date

November 18, 2019

Symposium organizers Jerold Chun (fourth from right), Randal Kaufman (second from left), Barbara Ranscht (third from right) and Huaxi Xu (far left), pose with the speakers

A mother who no longer remembers her son. A daughter who took doctor-prescribed pain medication and slipped into addiction. A father who has trouble grasping a pen and eventually becomes unable to walk. Neurological disorders are some of the most painful and complex conditions our society faces today. Yet much about the brain remains unknown, hindering our ability to help people with these disorders.

To help shed light on the brain’s mysteries, on November 1, 2019, more than 250 neuroscientists gathered at Sanford Burnham Prebys’ one-day symposium to share their latest discoveries. Organized by professors Jerold Chun, MD, PhD; Randal Kaufman, PhD; Barbara Ranscht, PhD; and Huaxi Xu, PhD, the event attracted scientists from around the world eager to learn more about biological clues that are leading to effective therapies. Read the full list of the invited speakers and their talks.

“Nearly every day we read about the toll neurological diseases such as Alzheimer’s, dementia, mental health disorders and more take on our society,” said Kristiina Vuori, MD, PhD, president of Sanford Burnham Prebys, in her introductory address. “Our symposium brings together scientists at the frontiers of brain research who share their latest discoveries to open new paths toward new and better treatments.”

More than 50 million Americans are affected by neurological disorders, including Alzheimer’s disease, dementia, addiction and more, according to the National Institute of Neurological Disorders and Stroke. Most of these conditions are not well addressed by current medicines.

At the symposium, world-renowned scientists from Stanford University, Mount Sinai, University of Vienna and other top-tier institutes gave talks describing their strategies to uncover the molecular basis of brain disorders and how these discoveries are advancing potential therapies. A national plan to address Alzheimer’s and other dementia types was described by Eliezer Masliah, MD, the National Institute of Aging’s director of the Division of Neuroscience.

“This was my first scientific conference, and it was perfect for learning about a wide range of cutting-edge brain research,” said attendee Jaclyn Beck, a PhD student at UC Irvine who studies the role of the brain’s immune cells, called microglia, in Alzheimer’s disease. “I have several pages of notes from the talks detailing findings I want to investigate and people I want to contact.”

For the past 40 years, our Institute has invited leading experts on one scientific topic to share their latest research at an annual symposium. By encouraging connection and collaboration, we hope to inspire insights that improve human health. The 41st annual symposium will take place in November 2020 and focus on the biology of organelles, specialized pouches within cells that carry out critical functions such as generating power and breaking down waste, and its role in health and disease.

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10 questions for Alzheimer’s expert Jerold Chun of Sanford Burnham Prebys

AuthorMonica May
Date

September 21, 2019

Jerold Chun, MD PhD

Alzheimer’s is one of the most frightening diseases of our time. Of the top 10 causes of death in the U.S., it is the only disease for which no effective or preventative treatment exists. Recent clinical trial failures have only deepened the pain of patients and their families.

To learn about the state of Alzheimer’s research in the wake of these setbacks—and whether there is hope on the horizon—we caught up with Alzheimer’s expert Jerold Chun, MD, PhD, professor and senior vice president of Neuroscience Drug Discovery at Sanford Burnham Prebys. Chun and his team recently published a Nature study that suggests a potential Alzheimer’s treatment may be closer than we think. 

  1. Why has Alzheimer’s disease become so prevalent? Are we better at diagnosing the disease?
    The number of people with Alzheimer’s disease is rising because of the aging Baby Boomers generation—which makes up more than 20% of the U.S. population. As a result, the number of those living with the condition is projected to more than double by 2050 to nearly 14 million people. This will place an incredible economic and social burden on our society—unless a treatment is found.
  2. Are there any treatments that work for Alzheimer’s disease?
    No disease-modifying therapies exist. The medicines a patient can receive today just treat symptoms. For example, cholinesterase inhibitors and N-methyl D-aspartate antagonists treat cognitive symptoms, such as memory loss, confusion and problems with thinking and reasoning—but they aren’t able to stop the disease. 
  3. Is it possible to prevent Alzheimer’s?
    Multiple studies from this year’s Alzheimer’s Association International Conference centered on this topic. Evidence suggests that adopting healthy lifestyle choices such as eating a healthy diet, not smoking, exercising regularly and stimulating the mind may decrease the risk of cognitive decline and dementia.

    It is encouraging to know that preventing Alzheimer’s may be partially within our control. However, it is undeniable that even individuals who live a healthy lifestyle will still develop Alzheimer’s. We need to remain laser focused on developing effective preventions and treatments.

  4. Do we know the cause of Alzheimer’s? What are the latest theories?
    In short, no. We know that clumps of amyloid-beta and tau proteins in the brain are linked to the disease. We also know that in rare cases genes are involved, because Alzheimer’s can run in families—but this accounts for less than 1% of cases. New research points to unique gene changes within the brain, called somatic gene recombination, as a new potential factor. Some data also implicate aspects of the immune system. It’s most likely that multiple factors lead to disease—and that an effective treatment will tackle Alzheimer’s from several angles.
  5. How would you describe the pipeline of Alzheimer’s treatments in development?
    The pipeline of Alzheimer’s treatments is in dire need of expansion. As of February 2019, only 132 drugs were under evaluation in clinical trials. Nearly half of these compounds target beta-amyloid. 

    For comparison, there are nearly 4,000 compounds under development for cancer—which affects almost three times as many Americans each year. We certainly need to continue to invest in cancer treatments—but clearly there is an urgent need to fill the Alzheimer’s pipeline, and an even greater need to find an approach that actually works.

  6. Tell us more about your research. What did you find? What are the next steps? 
    In school we learned that all cells have the same DNA. However, in our recent research we found that in the brains of patients, the DNA in the Alzheimer’s-linked APP gene can be “mixed and matched” into many different, new forms, some of which aren’t found in healthy individuals. To create these new gene variants, reverse transcriptase—best known as an enzyme infamously used by HIV—is required. This suggests that existing HIV medications—called reverse transcriptase inhibitors—which halt reverse transcriptase, might be useful as a near-term treatment for Alzheimer’s disease. A doctor can prescribe these medicines now as an “off-label” use for the treatment of Alzheimer’s disease. However, prospective clinical trials are needed to test the efficacy and side-effect profiles of these medicines in actual Alzheimer’s disease patients.
  7. Are humans the only species that get Alzheimer’s disease? 
    To our knowledge, yes. No other animal has the intellectual and cognitive capacity exhibited by humans. For this reason, scientists have developed animal models that exhibit symptoms and pathologies that approximate the disease. 
  8. How far away are we from an effective Alzheimer’s treatment? Years or decades? 
    What excites me about my team’s findings is that, if true, a partially effective treatment may be available now. Reverse transcriptase inhibitors are medicines currently used to treat HIV and hepatitis B, and have been safely used for 30 years with millions of patient-years of experience. New medicines based on this approach could lead to next-generation drugs with better efficacy and safety.

    Other agents in the Alzheimer’s pipeline currently in development are many years away from an effective treatment. And, it could take an additional 30 years for such agents to have the same level of proven safety as reverse transcriptase inhibitors. Nevertheless, new therapeutics must be pursued. Hopefully, our adult children will have great medical options in their future.

  9. What is the biggest hurdle to developing an Alzheimer’s treatment? 
    A major hurdle is securing funding for early, innovative research. The National Institutes of Health (NIH) is granting more funding than ever before to tackle this disease. However, many people aren’t aware that the NIH overwhelmingly finances projects that are scientifically conservative, which in the case of Alzheimer’s disease has failed to produce effective medicines. Funding that enables scientists to explore new, bold frontiers can be transformational in leading to important advances. This is an area where philanthropic donations can have a major impact—especially now, as the field strives to “think outside of the amyloid box” and explore new approaches.
  10.  Are you hopeful for the future? Why or why not?
    I am absolutely hopeful for the future. Advances in fundamental brain science will lead to new treatments for Alzheimer’s disease. Our work will hopefully be a start to a world where our children don’t have to live in fear of this disease.

About Jerold Chun 
Jerold Chun, MD, PhD, is a world-renowned neuroscientist who seeks to understand the brain and its diseases. His research has discovered genomic mosaicism and somatic gene recombination, surprising phenomena whereby cells in the brain actually have different genomic DNA sequences that can change with disease states. Chun’s research continues to shed light on Alzheimer’s disease, Parkinson’s disease, multiple sclerosis and other neurodegenerative diseases as well as neuropsychiatric disorders and substance abuse.

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Antimicrobial protein implicated in Parkinson’s disease

AuthorMonica May
Date

July 17, 2019

Myeloperoxidase enzyme

An immune system protein that usually protects the body from pathogens is abnormally produced in the brain during Parkinson’s disease, scientists from Sanford Burnham Prebys report. The discovery, published in Free Radical Biology & Medicine, indicates that developing a drug that blocks this protein, called myeloperoxidase (MPO), may help people with Parkinson’s disease.

“Prior to this study we knew that MPO was a powerful oxidizing enzyme found in white blood cells used to protect us from microbial infections,” says Wanda Reynolds, PhD, senior author of the study and adjunct associate professor at Sanford Burnham Prebys. “This is the first time that scientists have found that MPO is produced by neurons in the Parkinson’s disease brain, which opens important new directions for drug development.

Parkinson’s disease occurs when the neurons that control movement are impaired or destroyed. Over time, people with the disease lose mobility. The disorder affects men more than women; most people develop the disease around age 60. Currently available medicines address the disease’s symptoms, not the root cause. There is no cure.

“For this research we compared brain samples from people who had succumbed to Parkinson’s disease to those from normally aged brains,” says Reynolds. “We found that MPO was only expressed in neurons in people who succumbed to Parkinson’s disease—and not the healthy samples. 

“We then created unique mice that modeled Parkinson’s disease and expressed MPO. These mice accumulated toxic, misfolded proteins in the brain. Additionally, the MPO produced in the brain had an altered shape. As a result, instead of being stored inside neurons, MPO is capable of being ejected from the cell and cause further brain damage. We also found that MPO was located preferentially in the memory-associated regions of the brain—the cortex and hippocampus—indicating it plays a role in memory disruption.” 

Reynolds and her team are already working to develop an MPO inhibitor, which they hope will slow the progression of Parkinson’s disease. Based on Reynold’s previous research showing that MPO is abnormally expressed in the Alzheimer’s disease brain, an MPO inhibitor may also hold potential as an Alzheimer’s disease treatment. 

The first author of the study is Richard A. Maki, PhD, of Sanford Burnham Prebys. Additional authors include Michael Holzer, PhD, Gunther Marsche, PhD, and Ernst Malle, PhD, of the Medical University of Graz; Khatereh Motamedchaboki of Sanford Burnham Prebys; and Eliezer Masliah, MD, of the National Institutes of Health (NIH) and University of California, San Diego.

This work was supported by the NIH (ROINS074303, ROIAG017879, and ROI AG040623) and the Austrian National Bank (17600). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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SBP scientist awarded BrightFocus Foundation grant to advance Alzheimer’s research

AuthorMonica May
Date

August 21, 2018

Headshot of Yingjun Zhao, research assistant professor at SBP

The BrightFocus Foundation, a nonprofit working to end diseases of mind and sight, has awarded a two-year grant to Yingjun Zhao, PhD, research assistant professor at Sanford Burnham Prebys Medical Discovery Institute (SBP). This funding will advance Zhao’s study of a protein associated with memory loss in Alzheimer’s disease, called appoptosin. 

Alzheimer’s disease is a growing epidemic. In the U.S. alone, more than 5 million people over age 65 are living with the disease. In thirty years, as the population ages, scientists expect this number will nearly triple to 14 million Americans—unless we find a prevention or treatment. 

The protein Zhao studies, appoptosin, regulates cell death. His previous work showed the protein exists at higher levels in people with Alzheimer’s disease. Removing the protein slowed memory loss in mice—indicating it has therapeutic potential. Now, this grant will allow Zhao to better determine the link between appoptosin and memory loss in Alzheimer’s disease. The outcome of the research could yield new therapeutic targets for Alzheimer’s—valuable insights for scientists on the hunt for new treatments.

“Most studies focus on memory formation, but people with Alzheimer’s

Emotional photo of Yingjun Zhao, research assistant professor at SBP, with baby son ​
    Zhao and new arrival, Harry. 

have trouble both forming and keeping memories. Our work focuses on forgetting,” says Zhao. “We hope new leads for drug development will arise from this research, which will offer hope for people with Alzheimer’s and their caregivers. Thank you to the BrightFocus Foundation for supporting this important research.” 

Zhao has another milestone to celebrate: He recently welcomed his second child. As a father, this work takes on special meaning for Zhao. “I hope one day not only my children—but everyone’s children—can live a life free from Alzheimer’s disease,” he says. 

Read more information about the grant. 

Interested in keeping up with SBP’s latest discoveries, upcoming events and more? Subscribe to our monthly newsletter, Discoveries.

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Brain map connects brain diseases to specific cell types

AuthorSusan Gammon
Date

January 8, 2018

Astrocyte cells

Researchers have developed new single-cell sequencing methods that could be used to map the cell origins of various brain disorders, including Alzheimer’s, Parkinson’s, schizophrenia and bipolar disorder.

By analyzing individual nuclei of cells from adult human brains, Jerold Chun, MD, PhD, professor at SBP, in collaboration with researchers at UC San Diego and Harvard Medical School, have identified 35 different subtypes of neurons and glial cells and discovered which of these subtypes are most susceptible to common risk factors for different brain diseases.

There are multiple theories regarding the roots of brain diseases. The new study, published in Nature Biotechnology, allows scientists to narrow down and rank the cell types in the brain that carry the most genetic risk for developing brain disorders. The information can guide researchers to pick the best drug-targets for future therapies.

The work builds off of a previous study by the authors that identified 16 subtypes of neurons in the cerebral cortex. That study was the first large-scale mapping of gene activity in the human brain and provided a basis for understanding the diversity of individual brain cells.

In the new study, researchers developed a new generation of single-cell sequencing methods that enabled them to identify additional neuronal subtypes in the cerebral cortex as well as the cerebellum, and even further divide previously identified neuronal subtypes into different classes. The new methods also enabled researchers to identify different subtypes of glial cells, which wasn’t possible in the previous study due to the smaller size of glial cells.

“These data confirm and significantly expand our prior work, further highlighting the enormous transcriptional diversity among brain cell types, especially neurons,” says Chun. “This diversity, which continues to emerge from our single-cell analytical approach, will provide a foundation for better understanding the normal and diseased brain.” The advance was made possible by combining next-generation RNA sequencing with chromatin mapping—mapping of DNA and proteins in the nucleus that combine to form chromosomes—for more than 60,000 individual neurons and glial cells.

“While the analysis of RNA can tell us how cell types differ in their activity, the chromatin accessibility can reveal the regulatory mechanisms driving the distinctions between different cells”, notes Peter Kharchenko, PhD, an assistant professor of biomedical informatics at Harvard Medical School who co-led the study.

Using the information from RNA sequencing and chromatin mapping methods, researchers were able to map which cell types in the brain were affected by common risk alleles—snippets in DNA that occur more often in people with common genetic diseases. Researchers could then rank which subtypes of neurons or glial cells are more genetically susceptible to different brain diseases. For example, they found that two subtypes of glial cells, microglia and oligodendrocytes, were the first and second most at risk, respectively, for Alzheimer’s disease. They also identified microglia as most at risk for bipolar disorder, and a subtype of excitatory neurons as most at risk for schizophrenia.

“Now we can locate where the disease likely starts,” says Kun Zhang, PhD, professor of bioengineering at the UC San Diego Jacobs School of Engineering and co-senior author of the study. “However, we are only mapping the genetic risk. We don’t know the precise mechanism of how these specific cells actually trigger the disease.”

One caveat of this study, explains Zhang, is that it primarily analyzed data from adult brains (ages 20 to 50), so the findings do not represent younger or older populations. In order to better understand brain disorders that manifest early on, for example in infants, like autism spectrum disorder, the study would need to analyze cells from younger brains, he said.

The team also plans to expand their studies to map additional regions of the brain.

Authors of the study are Blue B. Lake*, Song Chen*, Brandon C. Sos*, Thu E. Duong, Derek Gao and Kun Zhang of UC San Diego; Jean Fan* and Peter V. Kharchenko of Harvard Medical School; and Gwendolyn Kaeser, Yun C. Yung and Jerold Chun of Sanford Burnham Prebys Medical Discovery Institute.

*These authors contributed equally to this work.

This story is based on a UC San Diego press release written by Liezel Labios.