Congratulations to Professor Tsuneya Ikezu and Colleagues for Selection in the Neuroscience 2014 Press Conference
Tau’s Role in Neurodegeneration
Microglia and exosome-mediated spread of pathogenic tau in Alzheimer’s disease
Our study suggests that microglial uptake and spreading of tau protein may play an important role in Alzheimer’s disease. Alzheimer’s disease is a neurodegenerative disease that affects more than 5.3 million people in the United States. The average life expectancy is eight to 10 years after onset, and there is currently no preventive or curative drug for this devastating disease. Alzheimer’s disease is characterized by the two different globs of proteins: beta-amyloid plaques and neurofibrillary tangles.
This study focuses on neurofibrillary tangles, which comprise aggregates of a protein called tau, normally attached to the cytoskeleton to build and maintain nerve cell structure. Tau accumulation first appears in the specific human brain region called the transentorhinal cortex before the onset of symptoms, and then gradually spreads to the hippocampal region. Because the hippocampus is important for learning and memory, the spread of tau protein in this region is associated with the early signs of Alzheimer’s disease. The mechanism by which tau protein spreads in specific brains is one of the hottest topics in the Alzheimer’s disease research field. Halting this spread before the onset of disease symptoms is a promising preventive intervention for the disease.
We hypothesize that brain immune cells called microglia engulf tau-containing synapses, or nerve cell bodies, and secrete tiny particles containing the tau protein. These particles are called exosomes, which are small vesicles of 50-100 nm in diameter and contain many messenger molecules and brain disease-linked proteins such as prion protein and alpha-synuclein. Exosomes can spread tau protein to other nerve cells and may serve as seeding molecules for inducing the aggregation of tau protein in the recipient cells. This microglial uptake and spreading of tau may play an important role in neurofibrillary tangle development.
Overall, our study demonstrates that exosomes and microglia are important mediators for spreading the pathogenic tau protein in tissue culture and animal models. Therefore, this study is highly significant not only to Alzheimer’s disease, but also to Pick’s disease and traumatic brain injury, in which neurofibrillary tangles also develop in the brain. In addition, this mechanism can be applied in understanding the spreading of other pathogenic molecules known to exist in the exosomes, such as prion protein for prion disease and alpha-synuclein for Parkinson’s disease.
*T. IKEZU1, H. ASAI2, S. IKEZU2, T. HAYDAR3, B. WOLOZIN1, S. KÜGLER4; 1Pharmacol. and Neurol., 2Pharmacol. and Exptl. Therapeut., 3Anat. and Neurobio., Boston Univ. Sch. of Med., Boston, MA; 4Ctr. for Nanoscale Microscopy and Physiol. of the Brain, Univ. Med. Göttingen, Göttingen, Germany
Presentation #: 578.08; Speaking Time: 11/18/2014 1:00:00 PM – 11/18/2014 3:00:00 PM
The neurofibrillary tangle is a pathological hallmark of Alzheimer’s disease (AD) and primarily consists of hyper-phosphorylated tau protein (pTau). pTau first appears in the entorhinal cortex in the presymptomatic stage, then gradually disseminates to the hippocampal region around the onset of clinical symptoms of AD. Halting this tau spread in the asympomatic stage is a promising therapeutic approach for AD. The exosome is a small vesicle of 50-100 nm in diameter, enriched in ceramide, and is suggested to contain neuropathogenic proteins, such as prion, α-synuclein, and recently tau proteins. A growing body of evidence suggests that microglia contribute to tauopathy-related pathogenesis in both human and animal models. We hypothesize that microglia transduce tau aggregates into nearby neuronal cells via exosomal secretion, and that inhibition of the exosome synthesis or secretory pathway reduces tau dissemination. We found that microglia efficiently phagocytose and secrete human tau aggregates in exosomes, which efficiently transduce tau aggregates in primary cultured mouse cortical neurons and induces accumulation of pTau. Moreover, we have created a novel mouse model exhibiting acute tau-spread by stereotaxic injection of adeno-associated virus expressing neuron-specific human mutant tau into the medial entorhinal cortex of mouse brain, which show spread of human tau to the granular cell layer of dentate gyrus at 28 days post injection. This tau spread was significantly suppressed by depletion of microglia or inhibition of neutral sphingomyelinase-2, which synthesizes ceramide and regulates exosome synthesis. These results demonstrate that microglia and exosomes play significant roles in spreading pathogenic tau in mouse brain. Our findings could lead to an entirely novel paradigm for delaying the progression of disease not only in AD but also other tauopathies such as FTD and chronic traumatic encephalopathy.
Congratulations to Maya in her selection to receive the SFN 2014 Graduate Student Travel Award. She is one of about 30 awardees in the nation!!
JEDI MIND Wins IARPA’s INSTINCT Challenge
WASHINGTON – The Intelligence Advanced Research Projects Activity (IARPA), within the Office of the Director of National Intelligence (ODNI), announced today the winner of its first public challenge contest, Investigating Novel Statistical Techniques to Identify Neurophysiological Correlates of Trustworthiness (INSTINCT). Troy Lau and Scott Kuzdeba’s winning solution, “JEDI MIND,” could drive further high-risk, high-payoff research on using one’s own neural, physiological, and behavioral signals to help anticipate other people’s intentions or behavior.
In JEDI MIND – Joint Estimation of Deception Intent via Multisource Integration of Neuropsychological Discriminators – Lau and Kuzdeba used a combination of innovative statistical techniques to improve predictions approximately 15% over the baseline analysis. They found that someone’s heart rate and reaction time were among the most useful signals for predicting how likely their partner was to keep a promise. The team’s combination of focused expertise with broader interdisciplinary interests helped them to address the complexities of the challenge—while both have experience with computational neuroscience, Lau is a Ph.D. physicist with a background in data mining and finance, and Kuzdeba is a research engineer with experience in statistical learning, various engineering applications, and economics. Both team members work in BAE Systems’ Adaptive Reasoning Technologies Group, located in Burlington, Mass.
Predicting one person’s trustworthiness from another’s signals is a difficult task, and IARPA chose the challenge format to solicit a wide range of statistical approaches to address it. “The overall structure of the challenge was a really positive and fun experience,” said Lau. “The crowdsourcing competition aspect was nice, but the way it was structured with five submissions per week and a real-time leaderboard was the best part. It made for some unique ‘instant gratification’ that is rare in research.”
Over the 70 days that the INSTINCT challenge was open, 39 solvers developed algorithms using the training set and then submitted algorithms to be scored against the test set. Seven of these exceeded baseline performance for the test data set, and their authors were invited to submit their “best and final” algorithm for independent evaluation against a third, non-released data set. Lower performance with new datasets is common, but JEDI MIND’s algorithms performed well on the new data set used for evaluation.
”We’re delighted with Lau and Kuzdeba’s insight into the data,” said Adam Russell, the TRUST program manager. “Their performance under the rigorous evaluation process of the INSTINCT Challenge provides additional evidence in support of one of the TRUST program’s basic hypotheses: that the self’s own, often non-conscious signals – if they can be detected and leveraged appropriately – may provide additional valuable information in trying to anticipate the intentions of others.”
Creating analysis techniques that generalize well is a major issue for many kinds of multimodal data sets and unsurprisingly was one of the largest hurdles for INSTINCT solvers. Although only one solver successfully overcame this barrier, all of the finalists produced innovative work and are to be commended. IARPA is currently assessing next steps for potential new research in this area based on lessons learned from the INSTINCT Challenge.
IARPA invests in high-risk, high-payoff research programs that have the potential to provide our nation with an overwhelming intelligence advantage over our future adversaries. Additional information on IARPA and its research may be found on iarpa.gov
BU’s Gloria Waters, Michael Hasselmo, and Timothy Gardner were among the academic, industry, and philanthropic leaders invited to the White House yesterday for a conference announcing stepped-up efforts to advance the president’s ambitious BRAIN (Brain Research through Advancing Neurotechnologies) Initiative. Waters, University vice president and associate provost for research, Hasselmo, a College of Arts & Sciences professor of psychological and brain sciences and director of BU’s new Center for Systems Neuroscience, and Gardner, a CAS assistant professor of biology and a College of Engineering assistant professor of biomedical engineering, were invited to the conference in recognition of BU’s commitment to the initiative.
“Last year I launched the BRAIN Initiative to help unlock the mysteries of the brain, to improve our treatment of conditions like Alzheimer’s and autism, and to deepen our understanding of how we think, learn, and remember,” Obama said. “I’m pleased to announce new steps that my administration is taking to support this critical research, and I’m heartened so see so many private, philanthropic, and academic institutions joining this effort.”
Obama’s BRAIN Initiative, which began as a $100 million project, aims to help researchers uncover the mysteries of brain disorders such as Alzheimer’s and Parkinson’s diseases, schizophrenia, and traumatic brain injury. At yesterday’s event, the White House announced an additional $300 million in support of the initiative, including $46 million in new National Institutes of Health grant awards, $30 million in research and development investments from GE, Google, GlaxoSmith Kline, and other companies, and $240 million in research efforts by major foundations, patient advocacy organizations, and universities, including BU. Brain researchers say the initiative has the potential to do for neuroscience what the Human Genome Project did for genomics by supporting the development and application of innovative technologies that can create a dynamic understanding of brain function.
“Our faculty are carrying out cutting-edge research in neuroscience, and we’re delighted to have our efforts in this area recognized,” Waters says. “Technologies for understanding the brain have advanced tremendously in the past decade, and we are hopeful that this work will lead to a better understanding of brain function, and ultimately, treatment for a wide range of brain disorders.”
In connection with the White House event, yesterday the NIH separately announced its initial $46 million in support of the BRAIN Initiative. Gardner, who records the neural activity of songbirds and was recently awarded a BU Innovation Career Development Professorship, is among the grant recipients. He was awarded nearly $1.8 million to develop a new technology for neural recording and stimulation based on dense bundles of ultrasmall fibers that increase the number of electrical channels while simultaneously minimizing tissue damage. A third of his grant will fund a collaborative project at the University of Texas, Dallas.
The NIH announced funding for 58 projects; the majority of them will focus on developing transformative technologies that will accelerate fundamental neuroscience research.
BU demonstrated its support for the BRAIN Initiative in 2014 by allocating $140 million for the creation of the Center for Integrated Life Sciences and Engineering (CILSE), which will bring together scientists and engineers from across the University for collaborative, interdisciplinary research in neuroscience and biological design.
CILSE will house the Center for Systems Neuroscience, launched this summer, and the new Center for Sensory Communication and Neuroengineering Technology, comprising neuroscientists who study communication systems, among them hearing, speech, language, vision, and other senses, as well as mathematicians studying neural coding and sensory physiologists who are developing innovative technologies. It will be directed by Barbara Shinn-Cunningham, an ENG professor of biomedical engineering, and will enhance technology development as well as work in areas such as neural prosthetics and brain computer interfaces. The University has committed an additional $4 million over five years to the launching of these neuroscience centers.
Ground will be broken at 610 Commonwealth Avenue in late spring or early summer 2015 for the state-of-the-art, nine-story CILSE building, which will cover 170,000 square feet and support about 20 faculty and some 400 students and staff. One of its core resources will be a cognitive neuroimaging facility, with a 3 Tesla fMRI scanner, a fundamental tool for studying the brain’s trillions of neural connections and how they relate to human behavior.
BU boasts one of the nation’s largest clusters of researchers in the emerging field of systems neuroscience, a field that examines the relation between molecular and cellular approaches to understanding brain structure and function, as well as the study of high-level mental functions such as language and memory.
“Consistent with the goals of the BRAIN Initiative,” Hasselmo says, “the goal of systems neuroscience at BU is to develop theories of how the brain functions based on data from recordings of different brain regions, using cutting-edge neurotechnology for measurement and testing of brain activity.”
Another leading BU neuroscientist, Xue Han, an ENG assistant professor of biomedical engineering, was among a group of neuroscientists invited to the White House in April 2013 for Obama’s initial announcement of the BRAIN Initiative.
Han is a pioneer in the young field of optogenetics, in which scientists reengineer nerve cells, or neurons, to respond to light, using molecules called opsins. The technique is now widely used to study brain activity, and she is using it to investigate Parkinson’s disease.
The White House also announced yesterday that the BRAIN Initiative is expanding to include five federal agencies, as the Food and Drug Administration and Intelligence Advanced Research Projects Activity join the NIH, the National Science Foundation, and the Defense Advanced Research Projects Agency. All of the participating agencies are committing to engage in BRAIN Initiative–related work in fiscal year 2015.
“How do the billions of cells in our brain control our thoughts, feelings, and movements? That’s ultimately what the BRAIN Initiative is about,” said Thomas R. Insel (CAS’72, MED’74), director of the NIH’s National Institute of Mental Health, who spoke at the White House yesterday. “Understanding this will greatly help us meet the rising challenges that brain disorders pose for the future health of the nation.”
Three Boston University GPN Neuroscientists Share Their Research on WBUR special series, “Brain Matters”
BU Neuroscientists Sam Ling, Xue Han and Tyler Perrachione featured on the WBUR special series “Brain Matters”
Congratulations to Samantha Michalka of the Somers Lab for winning first prize and Maripierre Payen Surpris of the Chen lab for second prize representing Graduate Program for Neuroscience at the MED campus!
Dr. Shelley Russek will represent GPN as a member of the Committee on Neuroscience Departments and Programs (CNDP) for the Society for Neuroscience. The mission of the CNDP is to enhance the value SfN provides to its individual and Institutional Program (IP) members (neuroscience departments and programs) through programs and initiatives that offer opportunities for professional development, networking, and information sharing to educators and learners in higher education.