Exosomes in the CNS

Exosomes in the CNS

Tuesday, March 21, 2017

The New York Academy of Sciences

Extracellular vesicles have experienced increasing attention in recent years, as our understanding of the diversity of their function has expanded from simple waste disposal units to critical players in cellular communication. In the brain, exosomes have been shown to convey signals between neurons and glia, influencing synapse biology, and may contribute to disease by modulating spread of alpha-synuclein and tau. This symposium will explore the role of extracellular vesicles in pathological processes underlying neurodegenerative disorders, and the appeal of exosomes as biomarkers and targets for the development of novel therapeutics.

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Agenda

* Presentation titles and times are subject to change.


March 21, 2017

11:30 AM

Registration

12:00 PM

Introduction and Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Tsuneya Ikezu, MD, PhD, Boston University School of Medicine

12:15 PM

Exosome Pathway as a New Therapeutic Target of Alzheimer’s Disease
Tsuneya Ikezu, MD, PhD, Boston University School of Medicine

12:45 PM

Secretion of Exosomes, a Neuroprotective Mechanism in Neurodegenerative Disorders
Efrat Levy, PhD, NYU School of Medicine

1:15 PM

Extracellular Vesicles as EVocators in Brain Tumors
Xandra Breakefield, PhD, Massachusetts General Hospital

1:45 PM

Networking Coffee Break and Poster Session

2:15 PM

Diagnosing Traumatic Brain Injury on a Chip via Circulating Exosomes
David Issadore, PhD, University of Pennsylvania

2:45 PM

Biomarkers in Urinary Exosomes for Neurological Diseases
Andrew West, PhD, The University of Alabama at Birmingham

3:15 PM

Prediction of Conversion from MCI to Dementia with Neuronally-Derived Blood Exosome Protein Profile
Robert A. Rissman, PhD, University of California San Diego, School of Medicine

3:45 PM

Closing Remarks and F1000 Outstanding Poster Prize

4:00 PM

Networking Reception

5:00 PM

Adjourn

Organizers

Mercedes Beyna, MS

Biogen

Mercedes Beyna, a researcher at Biogen, focuses on Drug Development mainly in the area of neurodegeneration. Captivated by neuroscience, she has worked in the field for over a decade, in both academic and industrial laboratory settings. Mercedes earned her undergraduate degree in Biology at Binghamton University and Master's Degree in Biology from New York University. As an active member of the Biochemical Pharmacology Discussion Group since 2010, she enjoys developing interesting and educational symposia.

Heike Hering, PhD

Biogen

Heike Hering is the head of the tau biology group within the Neurodegeneration & Repair unit at Biogen. Her team is focused on validating novel targets in the area of tau biology and advancing drug discovery projects towards novel therapies for the treatment of Alzheimer's Disease.

Before joining Biogen, as head of the in vitro neurobiology group Heike led a number of internal and external drug discovery projects for the treatment of Alzheimer's Disease and Multiple Sclerosis at the EMD Serono Research and Development Institute. Prior to this, she worked as Senior Scientist at Merck & Co. under the mentorship of Mike Hutton on tau related drug targets and at Memory Pharmaceuticals on the discovery of memory enhancing drugs.

Heike obtained her PhD from the Max-Planck Institute for Brain Research in Frankfurt, Germany, where she investigated the function of the extracellular matrix protein agrin during synapse formation in the vertebrate retina. Following her graduate training she conducted postdoctoral work in the laboratory of Morgan Sheng at the Massachusetts Institute of Technology in Cambridge, MA, where she studied novel molecular mechanisms of synapse formation and plasticity.

Tsuneya Ikezu, MD, PhD

Boston University School of Medicine

Sonya Dougal, PhD

The New York Academy of Sciences

Caitlin McOmish, PhD

The New York Academy of Sciences

Speakers

Xandra Breakefield, PhD

Massachusetts General Hospital
website

Xandra Breakefield, PhD is a research scientist with a strong background in molecular genetics and neuroscience. She has focused her efforts on: identification of neurologic disease genes, gene therapy for neurologic diseases; and elucidation of the role of extracellular vesicles (EVs) in cell-to-cell communication and tumor progression. In 2008 she led pioneering studies demonstrating mutant RNA in serum EVs from glioblastoma patients as biomarkers of disease status. She has published over 500 scientific articles and has received continuous support from the National Institutes of Health in the USA for her research over a 40 year period.

She did her undergraduate work at Wilson College and her graduate work in Microbial Genetics at Georgetown University. She was a Postdoctoral Fellow with Nobel Prize winner, Dr. Marshall Nirenberg at the NIH. She was appointed an Assistant Professor in the first Department of Human Genetics in the USA at Yale Medical School in 1974, and moved in 1984 to Harvard Medical School (HMS) and Massachusetts General Hospital (MGH). She is currently Professor of Neurology in the Neuroscience Program at Harvard Medical School and Geneticist in the Neurology and Radiology Services at Massachusetts General Hospital.

Professor Breakefield has received a number of awards for her work, including a McKnight Foundation Neuroscience Development Award, two Javits Neuroscience Investigator Awards, the Society for Neuroscience Mika Salpeter Lifetime Achievement Award, and the Harvard Medical School William Silen Lifetime Achievement Mentoring Award. She is a member of the American Academy of Arts and Sciences and past president of the American Society of Gene and Cell Therapy.

Tsuneya Ikezu, MD, PhD

Boston University School of Medicine
website

Tsuneya Ikezu, MD, PhD is a Professor of Pharmacology and Neurology at Boston University School of Medicine leads the Laboratory of Molecular NeuroTherapeutics. He has been investigating Alzheimer's disease (AD) over 20 years, and he has performed pioneering research into how modulation of neuroinflammation or neurogenesis enhances hippocampal function and ameliorates AD-like neuropathology through viral gene transfer system. He originally discovered caveolae as a platform of APP processing, cloned tau-tubulin kinase-1 as a neuron-specific tau kinase in AD, characterized anti-inflammatory cytokine therapy on hippocampal neurogenesis and cognitive enhancement in AD, and recently discovered new roles of microglia and exosomes for spreading of pathogenic tau protein in the brain. He has authored more than 70 journal articles, edited the textbook, Neuroimmune Pharmacology as a senior editor, and served on several editorial boards. Over his career, Dr. Ikezu has served on NIH Study sections and a recipient of Vada Kinman Oldfield Alzheimer's Research Award and Inge Grundke Iqbal Award from Alzheimer's Association. Dr. Ikezu received his MD/PhD from University of Tokyo School of Medicine, and completed post-doctoral trainings at Massachusetts General Hospital and Cleveland Clinic Foundation.

David Issadore, PhD

University of Pennsylvania

David is an Assistant Professor of Bioengineering and Electrical and Systems Engineering at the University of Pennsylvania. His research focuses on the integration of microelectronics, microfluidics, nanomaterials and molecular targeting, and their application to medicine. This multidisciplinary approach enables Issadore's lab to explore new technologies to bring medical diagnostics from expensive, centralized facilities, directly to clinical and resource-limited settings for applications including early detection of pancreatic cancer, Tuberculosis diagnosis in patients co-infected with HIV, and prognosis of traumatic brain injury. His academic background in electrical engineering and applied physics (PhD, Harvard 2009) and his research experience in a hospital research laboratory (MGH) have prepared him to work and collaborate effectively on these inherently cross-disciplinary problems.

Efrat Levy, PhD

NYU School of Medicine

My graduate studies were in cell biology, and my postdoctoral studies used molecular biological methods to identify the structure and evolutionary origin of the gene encoding mouse NF-M, the middle-molecular mass neurofilament protein. I then identified two human mutations that cause brain amyloidosis in effected individuals: a mutation in the cystatin C gene was identified as causing stroke in Icelandic patients with hereditary amyloid angiopathy, and the "Dutch" mutation in the amyloid β precursor protein gene was the first to be identified in a hereditary form of Alzheimer's disease. Since moving to the Nathan S. Kline Institute from New York University School of Medicine, the laboratory has continued investigating molecular and cellular factors that initiate and propagate pathology in neurodegenerative disorders, mainly Alzheimer's disease and Down syndrome. In vivo and in vitro systems are being used to examine pathogenic mechanisms in these diseases, including amyloidogenesis, endosomal-lysosomal and exosomal pathways functions, and the proteins that regulate and modify these events thereby identifying neuroprotective targets. Studies of brain extracellular vesicles suggest that depending on vesicular cargo, the exosomes can have either pathogenic function, propagating the disease within the brain, or neuroprotective and anti-amyloidogenic functions.

Robert A. Rissman, PhD

University of California San Diego, School of Medicine

Dr. Rissman is an Associate Professor in the Department of Neurosciences at the University of California, San Diego, School of Medicine. His work at UCSD is split into several parts that are balanced relatively equally. The goal of his basic science research is to investigate the contribution of stress and changes in stress signaling intermediates in Alzheimer's disease neuropathology. Using transgenic mice and in vivo pharmacology, experiments are focused on identifying the role of corticotropin-releasing factor (CRF) receptors in beta-amyloid deposition, tau phosphorylation and behavioral and synaptic changes. The Rissman lab is also examining human postmortem tissues to assay the specific changes that occur in the CRF signaling system during aging and Alzheimer's disease. In addition to this basic preclinical research program, Dr. Rissman is also the Director for the Alzheimer's Disease Cooperative Study (ADCS) Biomarker Core and the Neuropathology / Brain Bank for the Alzheimer's Disease Research Center (ADRC) at UCSD. Both cores include wet laboratories and biospecimen banks. Using bioassays and other analyses, the goal of the labs is to identify biomarkers for Alzheimer's disease and to better understand the impact of treatment parameters on these biomarkers. In addition to research, Dr. Rissman is the Principal Investigator for UCSD's Neuroplasticity of Aging Training Grant (T32) and teaches graduate classes on the Neurobiology of Disease. Dr. Rissman received his graduate degree in Neuroscience from Drexel University College of Medicine. He completed postgraduate training at the University of California, Irvine and at The Salk Institute.

Andrew West, PhD

The University of Alabama at Birmingham

Andrew West, PhD, is Co-Director of the Center for Neurodegeneration and Experimental Therapeutics (CNET) and Associate Professor at the University of Alabama at Birmingham (UAB). He joined the Department of Neurology in September of 2007 as the John A. & Ruth R. Jurenko Endowed Professor of Parkinson Disease research. Dr. West received his undergraduate degree from Alma College and his PhD in Molecular Neuroscience from the Mayo Clinic School of Medicine in Rochester, MN. He then went on to complete a Postdoctoral Fellowship at UCLA Neuropsychiatric Institute in Los Angeles and postdoctoral fellowship and Instructor position in Neurology at Johns Hopkins. The West Lab at UAB focuses on discovering the biochemical and genetic basis of neurological disorders such as Parkinson's disease and autism spectrum disorders.

Abstracts

Extracellular Vesicles as EVocators in Brain Tumors
Xandra O. Breakefield, PhD1

Glioma tumors release extracellular vesicles (EVs) in support of tumor progression. These EVs range in size from 100 nm to 1 µm and contain RNAs and proteins that can act as directives to cells in the tumor microenvironment. For example, tumor-derived EVs steer the transcriptome of neighboring microglia towards a more immune suppressive and tumor growth-promoting phenotype. This has been demonstrated by comparing microglia isolated from normal brains and from the brains of mice bearing syngeneic gliomas, with the latter microglia separated by FACS into those that have taken up fluorescently labeled tumor-derived EVs and those that have not. Work is also underway to try to harness these infiltrative packets of information as therapeutic vehicles to carry pro-drug activating enzymes/RNA which can deliver therapeutic drugs on site within the brain, thus avoiding the blood-brain barrier (BBB). Glioma cells have been genetically modified using lentivirus vectors to express RNA/proteins for cytosine deaminase::uracil phosphoribosyltransferase that are incorporated into EVs. These therapeutic EVs are taken up by non-modified tumor cells, with both tumor cell types subsequently being killed upon exposure to the prodrug, 5-fluorouracil. Thus although tumor-derived EVs are normally supportive for cancer, it may be possible to take advantage of their infiltrative and communicative properties and to arm them to act as therapeutic vehicles.
 
Coauthors: Sybren L. N. Maas, MD1, Erik R. Abels, MSc1, Joseph El Khoury, MD2, Kristina P. Friis, PhD1, Justin Hall1 and Marieke L. Broekman, PhD, MD1
 
1 Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital and Program in Neuroscience, Harvard Medical School, Boston, MA, USA
2 Department of Medicine, Harvard Medical School and Division of Infectious Disease, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA

Diagnosing Traumatic Brain Injury on a Chip via Circulating Exosomes
David Issadore1,2

Mild traumatic brain injury (mTBI) occurs in 2 million people annually. Most mTBI patients recover within one year, but 10% of mild cases result in a long-term disability. Although much is known about molecular changes in the brain following injury, access to biomarkers is lacking. Recently, brain-derived exosomes, which cross the blood-brain barrier and circulate following injury, have shown potential as a biomarker of brain recovery. Unfortunately, due to exosomes’ small size (30nm-200nm) and the scarcity of brain-derived exosomes, it has proven challenging to use these biomarkers to improve treatment. While microfluidics have been used successfully to precisely sort cells, scaling these approaches to exosomes has been limited by the low throughput and susceptibility to clogging of nanofluidics.
 
We solve this problem by developing a new approach to nanofluidic sorting of brain-derived exosomes, wherein millions of nanofluidic devices are incorporated onto a microchip platform and operated in parallel, increasing throughput by a million fold and eliminating susceptibility to clogging. Using our device, we isolate brain derived exosomes from V>10 mL serum and plasma in less than 15 minutes (> 6 hours using conventional methods), based on expression of brain-specific markers (GluR2). We incorporate our device with molecular analysis to profile exosomal nucleic acid cargo (miRNA). To validate clinical utility, we measured the exosomal RNA signature of healthy subjects and subjects with mTBI in two murine models and pilot clinical samples, and generated a predictive panel for post-concussion syndrome
 
Coauthors: Jina Ko1, Matt Hemphill1, Dave Meaney1
 
1 Department of Bioengineering, University of Pennsylvania, PA, USA
2 Department of Electrical and Systems Engineering, University of Pennsylvania, PA, USA

Secretion of Exosomes, a Neuroprotective Mechanism in Neurodegenerative Disorders
Efrat Levy, PhD1,2

Dysfunctional neuronal endosomes are an early characteristic of neurodegenerative diseases, including Down syndrome (DS) and Alzheimer’s disease. We hypothesized that endocytosed material is released by neuronal endosomal multivesicular bodies (MVB) into the extracellular space via exosomes to relieve the neurons of accumulated toxic endosomal content. We examined the level of extracellular vesicles (EV) and content in the brain of DS patients and a mouse model of the disease [Ts[Rb(12.1716)]2Cje] (Ts2Cje). In samples of frontal cortex of DS patients without amyloid pathology we found higher EV levels compared to age-matched diploid controls. Higher EV levels were also found in brain extracellular space of Ts2Cje mice compared to littermate controls. Examination of EV secretion into the media of cultured human fibroblasts showed that DS fibroblasts with endosomal abnormalities secrete higher levels of EV compared to age-matched 2N fibroblasts, revealing that higher levels of EV in the brain are due to enhanced secretion. Mass spectrometry identified significantly higher levels of exosomal markers in Ts2Cje EV compared to controls. mRNA and protein expression levels of the tetraspanin CD63, enriched in the membrane of MVB, were higher in DS brain homogenates and DS fibroblasts. To identify the mechanism for enhanced exosome secretion, we silenced CD63 expression and found diminished exosome release and impaired endosomes in DS fibroblasts. These data suggest that induction of CD63 expression enhances exosome release in DS brains, alleviating neuronal endosomal abnormalities, underscoring the regulation of exosome release as a therapeutic target for neurodegenerative disorders with endosomal pathology.
 
Coauthors: Rocío Pérez-González, PhD2, Sebastien A. Gauthier, PhD2
 
1 New York University Langone Medical Center, New York, NY, USA
2 Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA

Prediction of Conversion from Mild Cognitive Impairment to Dementia with Neuronally-Derived Blood Exosome Protein Profile
Charisse N. Winston, MS, PhD1

Levels of Alzheimer's disease (AD)-related proteins in plasma neuronal derived exosomes (NDEs) were quantified to identify biomarkers for prediction and staging of mild cognitive impairment (MCI) and AD
 
Plasma exosomes were extracted, precipitated, and enriched for neuronal source by anti-L1CAM antibody absorption. NDEs were characterized by size (Nanosight) and shape (TEM) and extracted NDE protein biomarkers were quantified by ELISAs. Plasma NDE cargo was injected into normal mice, and results were characterized by immunohistochemistry to determine pathogenic potential
 
Plasma NDE levels of P-T181-tau, P-S396-tau, and Aβ1-42 were significantly higher, whereas those of neurogranin (NRGN) and the repressor element 1-silencing transcription factor (REST) were significantly lower in AD and MCI converting to AD (ADC) patients compared to cognitively normal control subjects (CNC) and stable MCI patients. Mice injected with plasma NDEs from ADC patients displayed increased P-tau (PHF-1 antibody)-positive cells in the CA1 region of the hippocampus compared to plasma NDEs from CNC and stable MCI patients.
 
Abnormal plasma NDE levels of P-tau, Aβ1-42, NRGN, and REST accurately predict conversion of MCI to AD dementia. Plasma NDEs from demented patients seeded tau aggregation and induced AD-like neuropathology in normal mouse CNS.
 
Coauthors: Edward J. Goetzl, MD2, Jonny Akers, PhD1, Bob S. Carter, MD, PhD1, Edward Rockenstein, PhD1, Douglas R. Galasko, MD1, Eliezer Masliah, MD1 and Robert A. Rissman, PhD1
 
1 University of California, San Diego, La Jolla, CA, USA
2 University of California San Francisco, San Francisco, CA, USA

Exosome Pathway as a New Therapeutic Target of Alzheimer’s Disease
Tsuneya Ikezu, MD, PhD, Boston University School of Medicine, Boston, MA, USA

The neurofibrillary tangle is a pathological hallmark of Alzheimer’s disease and primarily consists of hyper-phosphorylated tau protein (pTau). pTau first appears in the entorhinal cortex in the pre-symptomatic 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 tau protein. Our recent study has shown 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. pTau was also identified in exosomes in the cerebrospinal fluid and plasma in Alzheimer’s disease patients, suggesting the potential value of exosomes as biomarkers of Alzheimer’s disease. These results demonstrate that exosome secretion from microglia play a significant role in propagation of tau protein, and that targeting this pathway may be beneficial in ameliorating disease progression.

Biomarkers in Urinary Exosomes for Neurological Diseases
Andrew B. West, PhD, University of Alabama at Birmingham, Birmingham, AL, USA

Exosomes, often referred to as ‘liquid biopsies’, encapsulate a pool of protein in biofluids that may be used to discover new biomarkers useful for disease prediction, progression, and response to therapies. Urine provides a non-invasively derived source of exosomes conveniently obtained from clinical populations that can be stored indefinitely. Urinary exosomes include robust concentrations of many proteins and their post-translational modifications, linked to neurological diseases. Our whole proteome scans of clinical populations reveal a subset of urinary exosome proteins that are stable over time and vary little between subjects, as well as proteins that are extremely variable over time and are often idiosyncratic. Within this spectrum lies a potentially rich source of proteins for biomarker studies. As a proof-of-principle, we identify a panel of urinary exosome proteins that can differentiate Parkinson disease cases from controls. In addition, analysis of the phosphorylation status of a single protein in urinary exosomes, LRRK2, demonstrates successful prediction of disease onset for carriers positive for the most common genetic cause of neurodegeneration. We propose that urinary exosomes may provide a rich source of proteins useful for understanding and treating CNS disorders.
 
Coauthors: James A. Mobley, PhD, Kyle B. Fraser, PhD, Shijie Wang, BS
University of Alabama at Birmingham, Birmingham, AL, USA

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