The Biology of Aging: Novel Drug Targets for Neurodegenerative Disease

The Biology of Aging: Novel Drug Targets for Neurodegenerative Disease

Friday, May 9, 2014

The New York Academy of Sciences

Age is the greatest risk factor for Alzheimer's disease. Key pathways within the biology of aging may represent important targets to develop novel and effective disease-modifying drugs to treat, delay, or prevent Alzheimer's and other age-related neurodegenerative diseases. In this 1-day conference, experts will present major recent advances in aging biology that represent important opportunities for drug discovery for Alzheimer's and other age-related neurodegenerative diseases. The first half of the day will focus on the basic biology of aging-related pathways, with one session on major circuits and a second session on novel targets and pathways. The second half of the day will focus on drug development programs for neurodegenerative disease based on targets identified from aging biology, including recent scientific advances in the science of autophagy, mitochondrial health, inflammation, and protein homeostasis.

*Reception to follow.

This event will also be broadcast as a webinar.

Please note: Transmission of presentations via the webinar is subject to individual consent by the speakers. Therefore, we cannot guarantee that every speaker's presentation will be broadcast in full via the webinar. To access all speakers' presentations in full, we invite you to attend the live event in New York City when possible.

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Member$30
Student/Postdoc Member$15
Nonmember (Academia)$65
Nonmember (Corporate)$85
Nonmember (Non-profit)$65
Nonmember (Student / Postdoc / Resident / Fellow)$45

 

Presented by

  • Alzheimer's Drug Discovery Foundation
  • The New York Academy of Sciences

The Brain Dysfunction Discussion Group is proudly supported by



Mission Partner support for the Frontiers of Science program provided by Pfizer

Agenda

* Presentation titles and times are subject to change.


May 9, 2014

8:00 AM

Registration and Continental Breakfast

8:45 AM

Welcome and Introduction
Howard Fillit, MD, The Alzheimer’s Drug Discovery Foundation
Kevin J. Lee, PhD, Lawrence Ellison Foundation
Jennifer Henry, PhD, The New York Academy of Sciences

Session I. Plenary Talk

9:00 AM

Delaying the Biology of Aging to Prevent Alzheimer's Disease
Nir Barzilai, MD, Albert Einstein College of Medicine

9:20 AM

Q&A Session

Session II. Major Pathways and Novel Targets in Aging Biology

9:30 AM

Autophagy, Cell Health and Aging
Eric Baehrecke, PhD, University of Massachusetts Medical School

9:50 AM

Q&A Session

10:00 AM

Aging and mTOR: Challenges in Sustaining Metabolic and Protein Homeostasis
Brendan D. Manning, PhD, Harvard University

10:20 AM

Q&A Session

10:30 AM

Coffee Break

11:00 AM

Proteostasis in Biology, Aging, and Disease
Richard Morimoto, PhD, Northwestern University

11:20 AM

Q&A Session

11:30 AM

The Complement Cascade and Cognitive Aging
Beth Stevens, PhD, Harvard Medical School

11:50 AM

Q&A Session

12:00 PM

Lunch Break

Session III. From Aging Biology to Drug Development for Neurodegenerative Disease

1:00 PM

The Anti Aging Protein Klotho as a New Target for Treating Neurodegenerative Diseases
Carmela Abraham, PhD, Boston University

1:20 PM

Q&A Session

1:30 PM

Stimulation of Macroautophagy with Small Molecules
Haung Yu, PhD, Columbia University

1:50 PM

Q&A Session

2:00 PM

A New Mitochondrial Target for Neurodegenerative Disease
Jerry Colca, PhD, Metabolic Solutions Development Company

2:20 PM

Q&A Session

2:30 PM

Coffee Break

3:00 PM

Targeting Neuroinflammation by Inhibiting Glial Cell Cytokine Production
D. Martin Watterson, PhD, Northwestern University Feinberg School of Medicine

3:20 PM

Q&A Session

3:30 PM

Biological and Chemical Approaches to Adapt Proteostasis to Ameliorate Protein Aggregation Diseases
Jeffrey W. Kelly, PhD, Scripps Research Institute

3:50 PM

Q&A Session

4:00 PM

Networking Reception

5:00 PM

Close

Speakers

Organizers

Howard Fillit, MD

Alzheimer's Drug Discovery Foundation

Howard Fillit, MD, a geriatrician, neuroscientist and a leading expert in Alzheimer's disease, is the founding Executive Director of the Alzheimer's Drug Discovery Foundation (ADDF). The ADDF's mission is to accelerate the discovery and development of drugs to prevent, treat and cure Alzheimer's disease, related dementias and cognitive aging. Dr Fillit has had a distinguished academic medicine career at The Rockefeller University and The Mount Sinai School of Medicine where he is a clinical professor of geriatrics and medicine and professor of neurobiology. He is a co-author of more than 250 scientific and clinical publications, and is the senior editor of the leading international Textbook of Geriatric Medicine and Gerontology. Previously, Dr Fillit was the Corporate Medical Director for Medicare at New York Life, responsible for over 125,000 Medicare managed care members in five regional markets. Dr Fillit has received several awards and honors including the Rita Hayworth Award for Lifetime Achievement. He also serves as a consultant to pharmaceutical and biotechnology companies, health care organizations and philanthropies.

Kevin J. Lee, PhD

Lawrence Ellison Foundation

Dr. Lee is Executive Director of the Lawrence Ellison Foundation, a philanthropic organization established to support biomedical research on the fundamental mechanisms of aging, age-related diseases, and neuroscience. The Lawrence Ellison Foundation is the philanthropy of Larry Ellison, founder and CEO of Oracle Corporation. 

Dr. Lee is a graduate of the University of Michigan and received his Ph.D. in biology from the Massachusetts Institute of Technology. His career spans over 25 years of research experience in molecular genetics and neurobiology in biotechnology, academic research and not-for-profit settings. He was appointed Executive Director of the Foundation in September 2012, having served as Deputy Executive Director from 2007-2012. Prior to joining the Ellison Medical Foundation, Dr. Lee served as Executive Vice President-Research of Sentigen Biosciences. He was responsible for the start-up and development of this New York City-based biotechnology company leading to its acquisition by Invitrogen Corporation in 2006. He has served as a member of the Scientific Review Board for the Simons Foundation Autism Research Initiative in New York. Dr. Lee's scientific research career employed genetic approaches to learn how neurons in the brain are "wired up" during development to make functional circuits that relay sensory information and control behavior. He worked with Dr. Thomas Jessell in the Center for Neurobiology and Behavior at Columbia University, where he studied the specification, axonal projection, and functional connectivity of nerve cells in the spinal cord. He is the recipient of biotechnology patents and is the author of numerous research publications.

Jennifer S. Henry, PhD

The New York Academy of Sciences

Speakers

Carmela R. Abraham, PhD

Boston University School of Medicine

Carmela R. Abraham obtained her PhD in Neuroscience at Harvard University. She then moved to Boston University School of Medicine where she is Professor of Biochemistry and Pharmacology & Experimental Therapeutics. Her laboratory studies the molecular mechanisms leading to normal brain aging and the pathological processes that culminate in Alzheimer's disease (AD). By utilizing the rhesus monkey as a model for understanding changes that occur during non-pathological aging her group discovered that the anti-aging protein Klotho is downregulated with age. Klotho is also significantly reduced in the AD brain but its function in brain was unknown. Dr. Abraham and her colleagues embarked on elucidating Klotho's role in the CNS. The group discovered that Klotho protects neurons against various insults, including the neurotoxic amyloid beta peptide, and oligodendrocytes, where Klotho induces their differentiation into myelinating cells. This is particular important in multiple sclerosis (MS) where oligodendrocyte progenitor cells fail to mature and produce myelin to repair demyelinated axons. As part of her translational research, Dr. Abraham identified small molecule compounds that enhance Klotho expression and plans to test them in mouse models of AD and MS. Dr. Abraham is the recipient of the Temple and Zenith awards from the Alzheimer's Association.

Eric H. Baehrecke, PhD

University of Massachusetts Medical School

Eric Baehrecke obtained his Ph.D. from the University of Wisconsin - Madison, and was a Howard Hughes Medical Institute Fellow of the Life Sciences Research Foundation at the University of Utah during his postdoctoral studies.  He was a faculty member of the University of Maryland from 1995-2007, and is currently Professor and Vice Chair of the Department of Cancer Biology at the University of Massachusetts Medical School. His team studies the regulation and function of autophagy in cell survival and cell death.

Nir Barzilai, MD

Albert Einstein College of Medicine

Dr. Barzilai  is a Professor of Medicine and Genetics and the Director of the Institute for Aging Research at the Albert Einstein College of Medicine the home of 2 Centers of excellence for the Biology of Aging. His interests focus on several basic mechanisms in the biology and genetics of aging. Among others, his studies on families with centenarians have provided genetic/biological insights on the protection against aging. Several drugs are developed based, in part, on these paradigm-changing studies. Dr. Barzilai was awarded over $35MM NIH funding for these efforts, has published over 200 peer-reviewed papers, and is a recipient of numerous prestigious awards, including the recipient of the 2010 Irving S. Wright Award of Distinction in Aging Research.  

Jerry R. Colca, PhD

Metabolic Solutions Development Company

Jerry Colca, PhD, is a co-founder, part owner, and President/Chief Scientific Officer of Metabolic Solutions Development Company (MSDC; msdrx.com) in Kalamazoo, MI.   Jerry has spent his professional career studying the endocrine control of metabolism as relates to diabetes.  He has a BS in Biology and MS and PhD in Physiology and Biochemistry from the University of Houston where he studied the regulation of secretion of pancreatic hormones.  His post doctoral training at Washington University  concentrated on the biochemistry of isolated pancreatic islets and the study of stimulus-secretion coupling in the control of metabolism.  Jerry joined the Upjohn Company in 1984 to study to the mechanism of action of the thiazolidinediones and was instrumental in selection and development of pioglitazone hydrochloride (Actos®) as an anti-diabetic agent through Phase 2A clinical studies.  The company formally known as Upjohn exited the insulin sensitizing field in 1993.  Jerry remained with the Upjohn Company through the mergers with Pharmacia, Monsanto-Searle, and Pfizer until he retired from the merged company in 2005.  During this time he was leader of diabetes discovery team in Kalamazoo, helped build  a new diabetes discovery effort in Sweden after the merger with Pharmacia, and finally building a new targets discovery effort in St. Louis after the Pfizer merger.  Jerry has been interested in the mechanism of action of the insulin sensitizer TZDs from the early days of their discovery and especially in the safety and pharmacology of pioglitazone.  In January of 2006, Jerry co-founded MSDC with Dr. Rolf Kletzien to take advantage of their unique insight into these molecules.  The company has now grown to have two compounds in clinical trials and is making significant progress into understanding the molecular mechanisms of the insulin sensitizers.  These efforts have identified a novel mitochondrial target through which new insulin sensitizers  coordinate  a pharmacology that can modify diseases of metabolic dysfunction.

Jeffrey W. Kelly, PhD

The Scripps Research Institute

Jeffery W. Kelly, PhD, is the Lita Annenberg Hazen Professor of Chemistry in the Department of Chemistry and the Chairman of the Department of Molecular and Experimental Medicine at the Scripps Research Institute. Kelly also served as Vice President of Academic Affairs and Dean of Graduate Studies at Scripps for nearly a decade. His research is focused on uncovering protein folding principles and on understanding the etiology of protein misfolding and/or aggregation diseases and using this information to develop novel therapeutic strategies. He has 290+ publications and has received several awards, including The American Chemical Society Ralph F. Hirschmann Award in Peptide Chemistry (2012), The Biopolymers Murray Goodman Memorial Prize (2012), The Protein Society Emil Thomas Kaiser Award (2011), The American Peptide Society Rao Makineni Lectureship (Award; 2011), The American Peptide Society Vincent du Vigneaud Award (2008), The American Chemical Society Arthur C. Cope Scholar Award (2001), State University of New York at Fredonia Alumni Distinguished Achievement Award (2000), The Protein Society-Dupont Young Investigator Award (1999) and The Biophysical Society National Lecturer (Award;1999). Kelly cofounded FoldRx Pharmaceuticals based on his discovery of Tafamidis-approved by the European Medicines Agency in 2011 and the Japanese authorities in 2013 to treat familial amyloid polyneuropathy. This first-in-class drug is the first pharmacologic agent that halts neurodegeneration in a human amyloid disease. Tafamidis or Vyndaqel also provides the first pharmacologic evidence that the process of amyloidogenesis causes the degeneration of post-mitotic tissue. He also cofounded Proteostasis Therapeutics, a company using small molecules to alter the protein homeostasis network to ameliorate several aggregation-associated degenerative diseases (e.g. Parkinson's) as well as loss-of-function diseases (Cystic Fibrosis). In 2012 Kelly Cofounded Misfolding Diagnostics, Inc., a San Diego company focusing on the early diagnosis of degenerative diseases.

Brendan D. Manning, PhD

Harvard School of Public Health

Brendan Manning received his Ph.D. from Yale University before joining the laboratory of Lewis Cantley at Harvard Medical School for his postdoctoral research.  During his time in the Cantley laboratory, he discovered that the tuberous sclerosis complex tumor suppressors are the key molecular connection between the PI3K and mTOR pathways, thereby linking a signaling pathway activated in the majority of human cancers to a nutrient-sensing pathway that controls cell growth and metabolism.  In 2004, Dr. Manning joined the faculty of the then newly established Department of Genetics and Complex Diseases at the Harvard School of Public Health, where he is now a professor and director of the Ph.D. Program in the Biological Sciences in Public Health.  Research in the Manning laboratory is focused on unraveling signaling networks that coordinate nutrient availability with metabolic responses and how dysregulation of such networks underlie aging and aging-related diseases.

Richard I. Morimoto, PhD

Northwestern University

Dr. Morimoto is the Bill and Gayle Cook Professor of Biology and Director of the Rice Institute for Biomedical Research in the Department of Molecular Biosciences at Northwestern University. He holds a B.S. from the University of Illinois at Chicago, a Ph.D. in Molecular Biology from The University of Chicago, and was a postdoctoral fellow at Harvard University. His research has been on the heat shock response, and the function of molecular chaperones and the proteostasis network in biology to maintain cellular health and to respond to challenges from environmental and physiological stress, aging and diseases of protein conformation. These studies provide a molecular basis for the cellular and organismal stress response and its role in aging and age-associated degenerative diseases including neurodegeneration, metabolic diseases, and cancer. Morimoto has published over 250 papers and edited five books. Some of the academic honors and awards include MERIT awards from the National Institutes of Health, elected membership in the American Association for the Advance of Science and the American Academy of Arts and Sciences, Commandeur, Ordre des Palmes Académiques (France), and the Fyodor Lynen Medal of the German Society of Biochemistry and Molecular Biology. He serves on Scientific Advisory Boards for the University of Heidelberg, RIKEN Brain Science Institute, Roswell Park Cancer Institute, BioCity Turku, and the Max Planck Institute. He is a co-founder of Proteostasis Therapeutics, Inc. a Biotech in Cambridge, MA to discover small molecule therapeutics for diseases of protein conformation.

Beth Stevens, PhD

Harvard Medical School

Beth Stevens received her PhD in Neuroscience in 2003 from the University of Maryland, College Park and completed her postdoctoral fellowship at the Stanford University School of Medicine in 2008. She is a recipient of several awards  including: the Smith Family Award for Excellence in Biomedical Research, Dana Foundation Award (Brain and Immunoimaging), Ellison Medical Foundation New Scholar in Aging award, John Merck Scholar Program.

D. Martin Watterson, PhD

Northwestern University Feinberg School of Medicine

Dr. Watterson holds the G.D.Searle Chair Professorship at Northwestern University where he founded a successful academic drug discovery program that brought CNS drug candidates to preclinical and clinical development. Administratively, he has served as a Department Chair, University Center Director and Curriculum Co-Director. His academic service record is complemented by commercial experience with small business start-ups, board of director service and pharmaceutical industry consulting.  Dr. Watterson directs an advisory group that assists companies, government agencies and research institutes in the processes of drug discovery and translation of basic science progress into clinically relevant deliverables. His previous academic appointments include faculty positions at The Rockefeller University, where he was an Andrew Mellon Fellow, and at Vanderbilt University Medical Center, where he was Professor of Pharmacology and an Investigator in the Howard Hughes Medical Institute.

Haung Yu, PhD

Columbia University

Dr. Wai Haung (Ho) Yu received his Ph.D. in Pharmacology from the University of Toronto and was a recipient of several awards including the Alzheimer Society of Canada Pre-doctoral award. Dr. Yu went to NYU/Nathan Kline Institute on a Canadian Institutes of Health Research Postdoctoral Fellowship and was a Clinical Instructor and then Assistant Professor prior to joining the Department of Pathology and Taub Institute for Research on Alzheimer's Disease and the Aging Brain at Columbia University (2006).

Dr. Yu's research interests include the role of protein quality control in neurodegeneration examining the biological outcomes of protein homeostasis in neurons and the deleterious effects of failed degradation primarily of aggregate-prone proteins like tau and α-synuclein. Dr. Yu's lab is developing novel neuronal assays and identifying new modulators of autophagic and lysosomal activity. Recent funding support includes NIH, Alzheimer Drug Discovery Fund (ADDF), CurePSP, Alzheimer's Association and BrightFocus. Dr. Yu has served on Scientific Review Boards for the Veteran's Administration, ADDF and W.G. Weston Foundation (Canada).

Sponsors

Bronze Sponsor

Takeda Pharmaceutical Company Limited

Academy Friend

Lawrence Ellison Foundation

Grant Support

This program is supported in part by a grant from Biogen Idec.

Promotional Partners

AlzForum

The American Academy of Neurology

American Federation for Aging Research

American Neurological Association

The Dana Foundation

European Federation of Neurological Societies

International Neuromodulation Society

Nature

SAGE Journals

Society for Neuroscience

Presented by

  • Alzheimer's Drug Discovery Foundation
  • The New York Academy of Sciences

The Brain Dysfunction Discussion Group is proudly supported by


  • Acorda Therapeutics

Mission Partner support for the Frontiers of Science program provided by Pfizer

Abstracts

Delaying the Biology of Aging to Prevent Alzheimer's Disease
Nir Barzilai, MD, Institute for Aging Research at Albert Einstein College of Medicine

Aging is the major risk not only for AD but also for other diseases such as cancer, type 2 Diabetes mellitus and cardiovascular disease. We hypothesize that a progress in preventing these diseases will occur only if we can understand the reason people age at different rates, and develop strategy to delay aging. We present 2 examples. We study the genome of centenarians, whose aging and onset of its diseases have been delayed. We have implicated a longevity genotype, cholesterol ester transfer protein (CETP), in the preservation of cognitive function in centenarians and their families. CETP inhibitor is in phase III trial to prevent CVD but offers an approach for prevention of AD. We have discovered line of, previously un-noted mitochondrial derived peptides, whose expression declines with aging. Those peptides have roles in metabolism and stress response. One of those peptides, humanin, has been directly implicated in neuronal toxicity relevant to AD. Derivation of this molecule is tested for potential drug development for AD. These examples suggest an approach of delaying aging and several of its disease, rather than focus on one organ-specific drug at a time.

Autophagy, Cell Health and Aging
Eric H. Baehrecke, Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605

Autophagy is a catabolic process that targets cytoplasmic components for degradation by the lysosome. Autophagy is an important cellular response to stress, and plays essential roles in development, aging, immunity, cancer and neurodegeneration. Thus, autophagy is considered a promising target for disease therapies. Studies of yeast led to the identification of conserved factors that regulate autophagy, but the role of autophagy in specific cell contexts during aging of multi-cellular organisms has not been rigorously studied. Recent studies of autophagy and how this process contributes to stem cell, tissue and organism health during aging will be presented.

Aging and Mtor: Challenges In Sustaining Metabolic And Protein Homeostasis
Brendan D. Manning, Ph.D, Harvard School of Public Health, Boston, MA

Metabolic processes within cells must be managed by integrated control mechanisms that sense the nutrient status of both the cell and organism. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a key signaling node, universal to eukaryotic cells, which links the sensing of nutrients to the coordinated regulation of cellular metabolism. mTORC1 has the ability to sense and integrate signals from a variety of sources, including intracellular nutrients and secreted growth factors. The physiological and pathological activation of mTORC1 results in downstream changes in cellular metabolism, with a shift from catabolic processes to anabolic biosynthetic processes. mTORC1 activity has been found in multiple species from yeast to mammals to contribute to aging, and mTORC1 is chronically activated in a variety of aging-related diseases. Through unbiased genomic and metabolomic approaches, we have found that, in addition to its established roles in promoting protein synthesis and inhibiting autophagy, mTORC1 stimulates changes in specific metabolic pathways through transcriptional and posttranslational effects on metabolic enzymes. In this manner, mTORC1 serves to link growth signals to metabolic processes that promote the growth of cells, tissues, and organisms, including the de novo synthesis of proteins, lipids, and nucleic acids. In addition, we have recently uncovered a novel and surprising role for mTORC1 in controlling cellular protein and amino acid homeostasis through the coordinated regulation of protein synthesis and degradation. This seemingly paradoxical function of mTORC1 serves as both a quality control mechanism to handle the increase in misfolded proteins that accompanies elevated rates of protein synthesis and as a means of maintaining adequate pools of intracellular amino acids to sustain new protein synthesis. The potential implications of these downstream functions of mTORC1 in understanding the pathological manifestations of aging will be discussed.

Proteostasis In Biology, Aging, And Disease
Richard I. Morimoto, Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA

The proteostasis network (PN) is essential for the health of the proteome, optimal tissue function, and lifespan.  Under ideal conditions, the PN prevents misfolding and aggregation that arises from genetic polymorphisms, error-prone synthesis, and mutations, that are exacerbated by stress, aging, and disease.  Critical components of the PN include the heat shock response (HSR), the unfolded protein responses, and antioxidant response that function in concert to protect the proteome against damage.  Despite these protective networks, the expression of 1/3rd of the human chaperome declines during brain aging and further in Alzheimer's, Huntington's and Parkinson's disease.  Functional RNAi assays with C. elegans models of Ab and polyQ expression revealed that a core chaperome of 16 genes are essential to prevent misfolding and proteotoxicity.  In C. elegans, this age-dependent decline in the HSR and other stress responses occurs abruptly upon reproductive maturity and appears to be regulated by epigenetic chromatin repressive marks that restricts the accessibility of HSF-1 to the promoter regions of HS genes.  At the organismal level, the transmission of stress signals across tissues involves cell non-autonomous signaling from the environment to sensory neurons to regulate the HSR of somatic tissues, and by transcellular chaperone signaling to achieve balanced organismal expression of chaperones between tissues expressing different levels of damaged proteins and altered levels of chaperones.  Orchestration of chaperone networks, therefore communicates the proteostatic state among cells and surrounding tissues, to adjust the PN throughout development and adulthood and to prevent the consequences of stress-induced proteotoxic damage.

Role of Complement Cascade in Synapse Loss and Cognitive Aging
Beth Stevens, Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115

Early synapse loss is a hallmark of aging and Alzheimer's disease (AD) but what makes synapses vulnerable remains elusive. During development, synapse pruning is a normal and highly regulated process, required for proper brain wiring and synaptic connectivity. Recent work has revealed unexpected roles for proteins of the classical complement cascade, an innate immune pathway, and microglia, immune cells that reside in the CNS, for elimination and refinement of synaptic connections in postnatal mouse brains. In developing brain, C1q and C3 are deposited onto less active synapses for elimination by microglia that express CR3. We hypothesized that similar mechanisms of synapse pruning may be involved to drive synapse loss in the aging brain and in the early stages of AD pathogenesis. We found an early, region-specific up regulation and deposition of complement (C1q) onto synapses in hippocampus and regions vulnerable to synapse loss, in two mouse models of Alzheimer's disease.  Preliminary results suggest genetic deletion of classical complement cascade components protect against early synapse loss and dysfunction in AD mouse models. Together our results suggest that aberrant reactivation of a normal developmental pruning pathway may work together to mediate early synapse loss in AD. . This study also has broad therapeutic implications for AD and other age dependent neurodegenerative diseases involving synaptic loss and dysfunction.

The Anti-Aging Protein Klotho as a New Target for Treating Neurodegenerative Diseases

Carmela R. Abraham, PhD1

In Alzheimer’s disease (AD), amyloid beta peptides (Ab) accumulate in the brain and are toxic to neurons and synapses. Strategies either to interfere with Aβ formation or enhance its clearance have not succeeded in slowing the progression of the disease. We propose a novel approach intended to protect neurons from the toxicity of Aβ and other age-related insults. Studying the anti-aging protein Klotho, our group has made four important discoveries that have profound relevance to AD and likely other neurodegenerative disorders. We found that: 1) the levels of Klotho, which protects mice and humans from aging and disease, are much lower in the aged healthy brain, in brains of AD patients and animal models of AD, 2) Klotho is able to rescue hippocampal neurons from Aβ and from oxidative stress and death induced by the excitotoxic amino acid glutamate, 3) a potentially novel molecular mechanism is responsible for the Klotho-induced neuroprotection, and 4) small molecule compounds that were developed from hits from a high throughput screen to enhance Klotho expression, can mimic Klotho’s neuroprotective functions and rescue neurons from death. Furthermore, Klotho induces the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes. This is particularly important for multiple sclerosis (MS) where there are plenty of OPCs around MS plaques, but where they fail to differentiate into mature myelin-forming cells. In summary, Klotho exhibits neuroprotective properties to neurons and promotes differentiation of oligodendrocytes and, therefore, Klotho enhancing small molecule compounds that cross the blood-brain barrier could become novel therapeutics for AD and MS.
 
Coauthors: Ci-Di Chen, PhD1, Marcie A. Glicksman, PhD2, Kevin Hodgetts, PhD2, Satish Medicetty, DVM, PhD3, and Ella Zeldich, PhD1
1Boston University School of Medicine, Boston, MA
2Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women’s Hospital, Boston, MA
3Renovo Neural, Inc., Cleveland, OH

Stimulation of macroautophagy with small molecules
Haung Yu, PhD, Yasir Qureshi, MD, Amanda L Chi, Matthieu Herman,
Taub Institute, Department of Pathology and Cell Biology, Columbia University

Autophagy is a major pathway for the clearance of redundant and aberrant proteins in cells, in addition to removal of defective organelles, like mitochondria. In neurodegenerative diseases like Alzheimer’s disease, this process may be inefficient and this can be attributed to a reduction in the amount of autophagy or a downstream disruption of autophagic-lysosomal processing. Using models of tauopathy, an investigation of small molecule activators of were investigated for their capacity to reduce phospho- and aggregated tau in cells and organotypic brain slice cultures from tau transgenic models. This presentation will discuss use of an organic molecule, trehalose, in addition to the identification of a lead compound and a series of modified structures for their capacity to induce autophagy. This study also demonstrates that upregulation of autophagy can successfully ameliorate proteinopathy and reduce the physiological and behavioral deficits associated with tauopathy.

A New Mitochondrial Target for Neurodegenerative Disease
Jerry R. Colca, Ph.D.Metabolic Solutions Development Company, Kalamazoo Michigan

Alzheimer's disease and other neurodegenerative diseases have a contributing metabolic dysfunction that includes a progressive loss of mitochondrial function.  This likely is a key reason while these diseases progress with aging.  It is also commonly observed that neurodegenerative diseases are associated with a phenomenon known as insulin resistance, where growth factor signaling is impaired.  Over the years, "insulin sensitizers" have shown positive results in preclinical models of neurodegeneration. We have recently found a previously unappreciated protein complex in the internal mitochondrial membrane that binds insulin sensitizing molecules.  This complex, which we have termed mTOT (mitochondrial target of the thiazolidinediones), includes key components of the mitochondrial pyruvate carrier as well as other important machinery that coordinates oxidative metabolism.  We have shown that treatment with a prototype mTOT modulator insulin sensitizer (MSDC-0160) maintains FDG-PET patterns patients with mild to moderate Alzheimer's in a three month clinical trial, indicative of central effects.  This presentation will summarize the results from this clinical trial and provide an update on the understanding of this new mitochondrial target. It is possible that modulation of metabolism with this pharmacology could provide a pathway to modify the course of neurodegenerative diseases.

Targeting Neuroinflammation by Inhibiting Glial Cell Cytokine Overproduction
D. Martin Watterson, PhD, Northwestern University Feinberg School of Medicine

Perturbation of homeostasis mechanisms critical to synaptic function is a component of pathology progression in diverse neurodegenerative diseases and the neurologic sequelae to brain injury. Stressor induced upregulation of proinflammatory cytokine production and the associated synaptic dysfunction is considered a key player in these mechanisms due to disruption of the glia-neuronal axis. Attenuation of the pathology progression offers the potential of disease modifying therapeutic intervention. We have applied a CNS focused drug discovery engine to the development of novel small molecule candidates that attenuate this injurious proinflammatory cytokine overproduction and the associated synaptic dysfunction. The discovery engine is a recursive, biology-driven chemistry platform that leverages small molecule pharmacoinformatics at the design and synthesis planning stage, and includes early pharmacological parsing of the novel synthesized compounds. The presentation will cover two distinct classes of drug candidates emerging from the application of this discovery engine. One class is a preclinical deliverable at the IND enabling stage that uses the popular single molecular target approach and employs high resolution co-crystallography and pharmacoinformatics based on small molecule CNS drugs. The second class that is in clinical trials stage emerged from the classical and more unbiased phenotypic approach with heavy dependence on pharmacoinformatics based on small molecule CNS drugs and re-utilization of validated CNS drug scaffolds. Both classes of compounds are orally active, brain-penetrant, small molecules that are selective, efficacious and safe in preclinical animal models of Alzheimer's disease. Our data suggest that selective targeting of the dysregulated cytokine response, a component of the neuroinflammation that contributes to synaptic dysfunction, is an attractive therapeutic strategy for neurodegenerative disorders such as Alzheimer's disease.

Biological and Chemical Approaches to Adapt Proteostasis to Ameliorate Protein Aggregation Diseases

Jeffery W. Kelly, Departments of Chemistry and Molecular and Experimental Medicine, and The Skaggs Institute of Chemical Biology, The Scripps Research Institute

The cellular protein homeostasis, or proteostasis network, regulates proteome function by controlling ribosomal protein synthesis, chaperone and enzyme mediated protein folding, protein trafficking, protein degradation and the like. Stress responsive signaling pathways match proteostasis network capacity with demand in each subcellular compartment to maintain cellular homeostasis. The beginning of the seminar will focus on how the proteostasis network can be adapted through unfolded protein response arm-selective signaling to alleviate gain-of-toxic-function diseases where excessive secretion of misfolding and aggregation of proteins leads to the amyloid diseases. The second part of the seminar will focus on a chemical strategy to achieve protein homeostasis, wherein small molecule kinetic stabilizers produced by structure-based drug design are employed to halt the progression of peripheral neuropathy in the human disease familial amyloid polyneuropathy linked to transthyretin amyloidogenesis. I will explain how delineating the molecular mechanism of transthyretin aggregation linked to pathology led to a regulatory agency approved drug. Since this is the first pharmacologic evidence supporting the amyloid hypothesis, the notion that protein aggregation causes degeneration of the heart and the nervous system, the last part of the seminar will focus on what we have learned about the etiology of these diseases vis-à-vis a successful clinical trial.

 

 

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