Translating Natural Products into Drugs for Alzheimer's and Neurodegenerative Disease

Translating Natural Products into Drugs for Alzheimer's and Neurodegenerative Disease

Monday, May 6, 2013

The New York Academy of Sciences

Historically, natural products have been a highly successful source for the development of new drugs. Alzheimer's and other neurodegenerative diseases are fraught with challenging drug targets that may benefit from the novel chemistries present in natural products. In addition, technological advances may present new opportunities for drug discovery based on natural product leads. This conference will present an overview of drug discovery from natural products, including novel approaches and technologies, and promising Alzheimer's drug discovery programs that originated from natural products.

*Reception to follow.

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Nonmember (Academia)$65
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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 times and titles are subject to change.


May 6, 2013

8:15 AM

Registration and Continental Breakfast

8:45 AM

Welcome
Jennifer Henry, PhD, The New York Academy of Sciences

8:50 AM

Opening Remarks
Howard Fillit, MD, The Alzheimer's Drug Discovery Foundation

Session I: Overview of Natural Product Drug Discovery

9:00 AM

Translating Natural Products into Drugs: Advantages, Disadvantages, and Historical Precedents
David J. Newman, PhD, National Cancer Institute, NIH

9:20 AM

Q&A session

9:30 AM

Natural Products Discovery — The State of the Art
Grant J. Carr, DPhil, AMRI

9:50 AM

Q&A session

10:00 AM

Medicinal Chemistry: The Challenges and Advantages of Natural Compounds
Frank E. Koehn, PhD, Pfizer Global R&D

10:20 AM

Q&A session

10:30 AM

Coffee Break

Session II: Natural Products for Alzheimer's Disease and Neurodegeneration

11:00 AM

The Origins of Galantamine
Bonnie M. Davis, MD, Synaptec

11:30 AM

HSP90 Inhibitors for Neurodegeneration — Geldanamycin as a Starting Point
Gabriela Chiosis, PhD, Memorial Sloan-Kettering Cancer Center

12:00 PM

Targeting Tau with Novel Marine-Sourced Natural Products and their Derivatives
Chad Dickey, PhD, University of South Florida

12:30 PM

Lunch Break

1:30 PM

Epothilone D: History and Future Directions in Alzheimer's Disease
Kurt R. Brunden, PhD, University of Pennsylvania

2:00 PM

Fingolimod Therapy for Multiple Sclerosis: A Fungal Derivative Mimicking a Natural Lipid
Jerold Chun, MD, PhD, The Scripps Research Institute

2:30 PM

Rapamycin as a Potential Therapeutic for Alzheimer's Disease
Salvatore Oddo, PhD, University of Texas Health Science Center, San Antonio

3:00 PM

Biologically Active Grape-Derived Polyphenols for Targeting Tau Oligomerization and Beta-Amyloidosis
Giulio Maria Pasinetti, MD, PhD, Mount Sinai School of Medicine

3:30 PM

Closing Remarks
Howard Fillit, MD, ADDF

4:00 PM

Networking Reception

5:00 PM

Close

Speakers

Organizers

Howard Fillit, MD

The 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 and treat 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 neuroscience. He is 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.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Kurt R. Brunden, PhD

University of Pennsylvania

Dr. Kurt R. Brunden is Director of Drug Discovery and Research Professor in the Center for Neurodegenerative Disease Research (CNDR) at the University of Pennsylvania, where he oversees drug discovery programs in the areas of Alzheimer's disease, frontotemporal lobar degeneration and Parkinson's disease. Prior to joining CNDR in 2007, Dr. Brunden served as a Vice President in two publicly-traded biotechnology companies, leading drug discovery and development programs in Alzheimer's disease, schizophrenia, metabolic disease, inflammation and oncology. Earlier in his career, Dr. Brunden was an NIH-funded faculty member within the Biochemistry Department at the University of Mississippi Medical Center. He obtained a BS degree (Magna Cum Laude) from Western Michigan University, with dual majors of Biology and Health Chemistry, a PhD in Biochemistry from Purdue University, and completed a post-doctoral fellowship at the Mayo Clinic. Dr. Brunden has >75 scientific publications and numerous issued and pending patents.

Grant J. Carr, DPhil

AMRI

Grant Carr has over 20 years in the biotech and pharmaceutical industries contributing to the development of therapeutic protein (Recombumin, Novozymes) and small molecule drugs (Odanacatib, Merck) and the discovery of a number of clinical candidates (for example CRA-028129, Schering AG). At AMRI Grant lead's the companies in vitro biology/pharmacology efforts (which he founded), natural product discovery based operations and the Bothell Research Center based to the NE of Seattle, WA. Grant has direct experience developing discovery strategies for a wide range of targets and therapeutic areas including CNS, diabetes, inflammation (CRA-028129), osteoporosis (Odanacatib) and cardiovascular disorders. More recently Grant led AMRI's efforts to discover novel antibacterial drugs to treat multi-drug resistant bacterial infections which ultimately led to the licensing of a compound series to Genentech in January 2011. Prior to joining AMRI Grant was the Director of Screening Operations at Elitra Pharmaceuticals where he reduced to practice a novel platform technology for the identification of antibacterial compounds with specific mechanisms of action utilizing hyper-sensitive cell based assays and co-invented a technology enabling the identification of the mechanism of action of any antibacterial compound. These inventions translated into collaborations with large Pharmas and the eventual acquisition of Elitra by Merck who continue to publish discoveries based on these technologies. Prior to joining Elitra Grant founded the HTS group at Arris taking on additional responsibilities over the years until he was the Director of Biochemistry responsible for the in vitro pharmacology of all of the companies programs including those contributing to the discovery of Odanacatib, a first in class Cathepsin K inhibitor for the treatment of osteoporosis, and the licensing of compounds for inflammation (CRA-028129, a Cathepsin S inhibitor, licensed to Schering AG) and thrombosis (a Factor Xa inhibitor series, licensed to Pharmacia).

Gabriela Chiosis, PhD

Memorial Sloan-Kettering Cancer Center

Dr. Gabriela Chiosis is a Principal Investigator and an Associate Member in the Program in Molecular Pharmacology and Chemistry at Sloan-Kettering Institute, and an Associate Attending in the Department of Medicine of Memorial Hospital for Cancer & Allied Diseases, New York. She is also a faculty in several biomedical graduate programs such as the Program in Pharmacology, Weill Graduate School of Medical Sciences, Cornell University, the Tri-Institutional Training Program in Chemical Biology, Sloan-Kettering Institute for Cancer Center, Cornell University and The Rockefeller University and the Cancer Biology Program of the Gerstner Sloan-Kettering Graduate School. She received her graduate training at Columbia University in New York and has joined Memorial Sloan-Kettering Cancer Center in 1998. The Chiosis Laboratory investigates the significance of modulating molecular chaperones in disease treatment. In this respect, it has developed pharmacological tools instrumental in defining the roles of Hsp90 in regulating the stability and function of aberrant protein driving the neurodegenerative phenotype in tauopathies. Hsp90 inhibitors discovered by the lab are the platform for the development of several purine-scaffold Hsp90 inhibitors currently in clinical evaluation in patients with advanced cancers.

Jerold Chun, MD, PhD

The Scripps Research Institute

Jerold Chun is a Professor in the Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, at The Scripps Research Institute (TSRI) and an Adjunct Professor of Pharmacology and Neuroscience at The University of California, San Diego (UCSD) School of Medicine. His laboratory identified the first lysophospholipid receptor and has contributed to understanding roles for this receptor family — that includes receptors for sphingosine 1-phosphate (S1P), the target for the Multiple Sclerosis drug fingolimod — in normal and diseased states. He received both MD and PhD (Neuroscience) from Stanford University School of Medicine, conducted postdoctoral work at the Whitehead Institute/MIT in Cambridge, MA, and subsequently has held positions of Professor at UCSD School of Medicine, Senior Director and Department Head (Molecular Neuroscience) at Merck, before joining TSRI.

Bonnie M. Davis, MD

Synaptec

Dr. Davis is the inventor of the use of galantamine (Reminyl, Razadyne) for Alzheimer's disease and related dementias. Her patents have been licensed to Ciba-Geigy (now Novartis), Hoechst Roussel (now Sanofi-Aventis), Johnson & Johnson and Shire. She is the founder and CEO of Synaptec, which is currently developing compounds as positive allosteric modulators of nicotinic receptors. Following an undergraduate degree in chemistry from Syracuse University, Dr. Davis earned an MD from the Mount Sinai School of Medicine, trained in internal medicine at Kaiser Hospital in Santa Clara, California, and performed early studies in insulin resistance as a fellow in Endocrinology and Metabolism at Stanford Medical Center. Dr. Davis joined the faculty of Mount Sinai in 1979, serving as the Medical Director of the Psychiatric Clinical Research Center, and conducting endocrine studies in Alzheimer's disease and schizophrenia. In 1988, she left Mount Sinai to raise her two children and to found Synaptec. She was elected to the Board of Trustees of the Mount Sinai Medical Center in 2007, where she chairs the committee on Technology Transfer.

Chad Dickey, PhD

University of South Florida

Dr. Chad Dickey joined the faculty at the Byrd Alzheimer's Institute in September 2008. Dr. Dickey earned his PhD from the University of South Florida under the direction of Dr. David Morgan in 2004. His post-doctoral training was done at the Mayo Clinic in Jacksonville under the direction of Dr. Michael Hutton, an expert in the field of Alzheimer's disease genetics. He was a recipient of a New Investigator Award from the Alzheimer's Association and a Rosalinde and Arthur Gilbert Foundation/AFAR New Investigator Award in Alzheimer's disease. Dr. Dickey has conducted two research projects for the Society for Progressive Supranuclear Palsy to study the mechanisms behind this particular form of hereditary dementia. He is currently funded through the NIH, the VHA, AHAF and AFAR for his research related to therapeutic development for and molecular mechanisms of Alzheimer's disease and tauopathies. He lives in the Carrollwood area of Tampa with his wife Adria and his two sons, Luke and Jacob.

Frank E. Koehn, PhD

Pfizer Global R&D

Frank E. Koehn, born in 1955, obtained his B.S. degree in Chemistry from Butler University, Indianapolis Indiana USA, and did his doctoral research on marine red tide neurotoxins at the University of Wisconsin-Madison, USA. Following postdoctoral work in natural products at the University of Pennsylvania, in 1984 he joined the Harbor Branch Oceanographic Institution in Fort Pierce, Florida, USA, where he spent the next decade studying biologically active marine natural products. He joined Lederle Laboratories in 1994, which subsequently became Wyeth Research. In 2010 he joined Pfizer as a Research Fellow, where his laboratory is focused on the application of natural products in new disease therapies.

David J. Newman, PhD

National Cancer Institute, NIH

David Newman is the current President of the American Society of Pharmacognosy for 2012-2013, and chief of the Natural Products Branch (NPB) in the Developmental Therapeutics Program at the National Cancer Institute in Frederick, MD. Born in the UK he received a MSc in synthetic organic chemistry from the University of Liverpool and a DPhil for work in microbial chemistry from the University of Sussex. He came to the USA in1968 as a post-doctoral fellow in the Biochemistry Department at the University of Georgia and in 1970 joined the then SK&F as a biological chemist. He later completed an MS in Information Science at Drexel University in Philadelphia, PA, and in 1985 he left SK&F when their antibiotic discovery program ceased. Following work in marine and microbial discovery programs at various companies he joined the NPB in 1991 with responsibilities for marine and microbial collection programs. He received the NIH Award of Merit in 2003 for the development of microbial and marine drug candidates at NCI, Following Gordon Cragg's retirement he was acting chief from Jan 2005 until appointed chief of the NPB in late 2006. His research interests are in natural product structures as drugs and leads thereto. He is the author or coauthor of over 150 papers, reviews and book chapters, and holds 21 patents mainly on microbial products.

Salvatore Oddo, PhD

University of Texas Health Science Center, San Antonio

Dr. Oddo received his undergraduate degree in Molecular Biology from the University of Catania, Italy, and his graduate degree in Neurobiology of Learning and Memory from the University of California, Irvine. Dr. Oddo's research focuses on understanding the molecular mechanisms underlying memory deficits in Alzheimer's disease. Using animal models, he showed that dysfunction signaling transduction pathways that are critical for learning and memory play a pivotal role in the cognitive decline associated with Alzheimer's disease. Currently, he is the Principal Investigator of a grant from the National Institute of Health, which is focused on elucidating the role of the mammalian target of rapamycin on the pathogenesis of Alzheimer's disease. Dr. Oddo has published more than 60 research articles in international peer-reviewed journals. In recognition of his contribution to the aging and Alzheimer's disease fields, he has been the recipient of several national and international awards.

Giulio Maria Pasinetti, MD, PhD

Mount Sinai School of Medicine

Dr. Giulio Maria Pasinetti's research on complementary and alternative medicine influencing clinical dementia, neurodegeneration and Alzheimer's disease has made him a pioneer in his field. He is the recipient of major awards as The Alzheimer's Association's Zenith Award and the Foundation Queen Sofia of Spain Research Center Award on Alzheimer's Disease, among others. Dr. Pasinetti is a Professor of Neurology, Psychiatry, Neuroscience, and Geriatrics and Adult Development, and is Chief of the Brain Institute Center of Excellence for Novel Approaches to Neurotherapeutics at Mount Sinai School of Medicine. He also serves as Director of the Basic and Biomedical Research and Training, Geriatric Education and Clinical Center at the Bronx Veterans Affairs Medical Center. Dr. Pasinetti recently received an NIH-funded research grant supporting a Center of Excellence for Research in Complementary and Alternative Medicine in Alzheimer's disease. Dr. Pasinetti is currently the Principal Investigator and Director of the Center.

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Alzheimer Research Forum

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Nature

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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

Translating Natural Products into Drugs: Advantages, Disadvantages, and Historical Precedents
David J. Newman, PhD, National Cancer Institute, NIH

Alzheimer's disease is one that has a variety of etiologies with the current "theory" heavily related to the presence of amyloid plaques in the brain of AD patients on autopsy. The current treatments are based on various acetylcholinesterase inhibitors, agents that alter Tau pathologies and agents claimed to be "neuroprotectives", and currently, there is significant interest in the production of ApoE (an apolipoprotein) in patients who are carriers of the gene ApoE4. Investigation of the natural product literature shows a very significant number of pure natural products (as distinct from food supplements, traditional remedies, etc.) that have been used as AChE inhibitors, tau-interference agents, secretase inhibitors and anti-inflammatories (due to the probable relationship between inflammation and neuronal damage). This short presentation will discuss the sources of some of the newer agents (or older agents with potential utility) from plant and marine sources, though there is a strong possibility that microbes are involved in some of the materials to be mentioned. There will also be a discussion of the problems associated with the use of pure natural products; for example source versus synthesis, making certain of supplies when having to source overseas. Examples to be presented will include the problems associated with taxol® (chemical relatives of which may be a potential treatment in due course) and how these can be overcome.
 

Natural Products Discovery — The State of the Art
Grant J. Carr, DPhil, AMRI

Natural product samples have been a rich source of therapeutic agents and starting points for successful lead optimization campaigns. Despite these successes interest in natural products discovery has diminished over the last 25 years to the point that today it is often viewed as the strategy of last resort by commercial enterprises. The drivers of this decline and the strategic and technological advances which are leading a return to prominence are presented.
 

Medicinal Chemistry: The Challenges and Advantages of Natural Compounds
Frank E. Koehn, PhD, Pfizer Global R&D

Natural products derived from plants, microbial fermentation and marine organisms are an unsurpassed source of lead structures for drug discovery. It is now apparent that these molecules offer a means of addressing previously "undruggable" target space. However, natural products are often difficult to advance in a lead development sense because of their complex chemical structures and often- limited availability. Chemical synthesis and now biosynthetic engineering of the producing host organisms offer means to modify natural product leads in ways which are not possible by chemical semisynthesis alone. This talk describes the current role of natural products in lead generation and goes on to describe cases where synthetic and biosynthetic medicinal chemistry have been used to advance natural product drug candidates.
 

The Origins of Galantamine
Bonnie M. Davis, MD, Synaptec

Man's appreciation of the medicinal value of galantamine may extend back to ancient Greece. It has been postulated that the milk-colored flower that Hermes gave to Odysseus to counteract the forgetful and delusional state caused by the potions of the nymph Circe was the snowdrop galanthus nivalis, a source of galantamine. Our current understanding of galantamine began with its isolation and characterization as an acetylcholinesterase inhibitor in the early 1950s. Soon after that, a direct effect on acetylcholine receptors of the skeletal muscles was appreciated. Galantamine's enhancement of the activity of carbachol, a cholinesterase-resistant acetylcholine analog, demonstrated that it was a sensitizer of the muscle receptor, the nicotinic receptor. It was galantamine's nicotinic properties that led it to be identified for use in Alzheimer's disease, based on endocrine changes dependent upon central nicotinic pathways. Galantamine owes its natural selection to the rapid creation of a transient, aversive, memorable, but not lethal experience for an animal who would ingest large amounts in a daffodil bulb. These properties are important to galantamine's clinical activity. Galantamine is well absorbed, crosses the blood–brain barrier, binds competitively to the enzymatic site on acetylcholinesterase, and to a positive allosteric modulatory site on nicotinic receptors, with little nonspecific binding. It has a physiologic half-life, compatible with physiologic cholinergic rhythms, and therefore does not induce substantial counter-regulatory acetylcholinesterase. Galantamine reduces loss of brain volume, cognition and activities of daily living in controlled two year trials. The experience of bringing a natural product to market will be presented.
 

HSP90 Inhibitors for Neurodegeneration — Geldanamycin as a Starting Point
Gabriela Chiosis, PhD, Memorial Sloan-Kettering Cancer Center

Hsp90 is a molecular chaperone with important roles in regulating pathogenic transformation. While the HSP90 protein was first discovered in the 1980s, it has drawn little interest as a potential target. After all it is abundantly and ubiquitously expressed in most if not all human cells, knockdown of even 50% has little phenotypic outcome whereas knock-out of the HSP90ß paralog is embryonically lethal. Such findings match poorly with the belief that a good therapeutic target has to be crucial to the disease phenotype and be of low expression in vital organs and tissues. Interest on the target potential of HSP90 grew however after the serendipitous discovery of a natural product, geldanamycin. While surprising in light of the available genetic data, low, non-toxic concentrations of this natural product led to a reversal of the disease phenotype and to neuroprotection in several models of neurodegenerative diseases, indicating that for HSP90, pharmacologic and genetic modulation have a distinct outcome. Indeed, much of our understanding on the distinct biology of HSP90 in neurodegeneration and other diseases comes from pharmacologic studies with geldanamycin and other much improved small molecule HSP90 inhibitors. These efforts elucidated a role for HSP90 in stabilizing mutated or abnormally-modified disease-causing proteins, and shed light on mechanisms behind the selective targeting by small molecule HSP90 inhibitors of "pathogenic" HSP90 species. The talk will give an overview of such concepts and present studies towards the potential translation of HSP90 inhibitors for the treatment of neurodegenerative diseases.
 

Targeting Tau with Novel Marine-Sourced Natural Products and their Derivatives
Chad Dickey, University of South Florida

Natural products chemistry has produced several effective Alzheimer's disease (AD) therapy leads, including the amyloid aggregation inhibitor, curcumin, isolated from turmeric; _ENREF_22 the microtubule stabilizer, paclitaxel from the Pacific yew tree; and the Streptomyces-derived Hsp90 inhibitor, geldanaymcin. In fact, ~60% of all therapeutics currently in use for human disease were derived originally from natural products. While most target-based drug discovery efforts in AD have centered on modulation of the amyloid β peptide, these have met with limited success in the clinic. Therefore, recent efforts have focused on targeting the microtubule-associated protein tau, which more closely correlates with the neuronal loss in AD. By analyzing extracts from natural sources with a modern cell-based screening platform that measures tau levels, we found that extract from Myrica cerifera (Bayberry/southern wax myrtle) potently reduced both endogenous and over-expressed tau protein levels in cells and murine brain. The bayberry flavonoids myricetin and myricitrin were confirmed to contribute to this potency but a diarylheptanoid, myricanol, was the most effective anti-tau component in the extract. (+)-S-myricanol isolated from M. cerifera was significantly more potent than commercially available (±)-myricanol. Myricanol may represent a novel scaffold for drug development efforts targeting tau turnover in AD. Through medicinal chemistry efforts, we have now developed a more stable and reliable derivative of (+)-S-myricanol that does not rely on chirality for its activity. Taking these efforts a step further, we have now turned our discovery platform towards a more novel collection of natural product extracts derived from cold water marine organisms recovered from the Southern/Antarctic Ocean. Initial work has identified that some of these extracts and purified compounds have very potent anti-tau efficacy. Efforts are underway to identify the active components of these extracts and understand their mechanism of action.
 

Epothilone D: History and Future Directions in Alzheimer's
Kurt R. Brunden, PhD, University of Pennsylvania

Neurons within the brains of those with Alzheimer's disease (AD) and other related neurodegenerative disorders contain inclusions comprised of hyperphosphorylated tau protein. Tau is normally enriched in axons, where it binds and stabilizes microtubules (MTs). In disease, tau hyperphosphorylation can promote its disengagement from MTs and subsequent aggregation, which likely leads to reduced MT stability that could negatively affect neuron function. Accordingly, a possible therapeutic strategy for AD and related "tauopathies" is the utilization of MT-stabilizing drugs, such as those currently used for the treatment of cancer. However, most existing MT-stabilizing agents are not suitable for brain disorders because of poor blood-brain barrier (BBB) permeability. We have identified epothilone D (EpoD), a compound previously tested in oncology clinical trials, as a brain-penetrant MT-stabilizing drug candidate with unique pharmacokinetic properties. This led to the testing of EpoD in an established tau transgenic mouse model with AD-like pathology, using both preventative and interventional dosing schemes. EpoD at doses that were a fraction of those used in human cancer clinical trials resulted in a normalization of axonal MT density and axonal transport in the tau transgenic mice. Moreover, EpoD reduced the extent of tau pathology in aged tau transgenic mice, with an improvement of cognitive performance. Importantly, no adverse side effects were observed in the EpoD-treated mice. These results suggest that EpoD might be a potential treatment for tauopathies, and this drug candidate is now undergoing clinical testing in AD patients.
 

Fingolimod Therapy for Multiple Sclerosis: A Fungal Derivative Mimicking a Natural Lipid
Jerold Chun, MD, PhD, The Scripps Research Institute

Fingolimod (also known as FTY720 and Gilenya (Novartis)) was FDA approved in 2010 as the first oral treatment for relapsing forms of Multiple Sclerosis (MS). MS is an autoimmune disorder that affects the central nervous system (CNS) and can result in neurodegeneration. Fingolimod arose from studies of fungal metabolic derivatives. It showed initial bioactivities affecting the immune system through an unknown mechanism of action. Subsequent work demonstrated that fingolimod was a chemical analog of a naturally occurring lipid known as sphingosine: upon in vivo phosphorylation, fingolimod-phosphate is produced which mimics sphingosine 1-phosphate (S1P), a member of the lysophospholipid group of signaling lipids. Lysophospholipids produce biological effects through a family of 7-transmembrane, G protein-coupled receptors that have broad tissue expression including the immune system and the brain. Fingolimod thus accesses S1P lysophospholipid signaling to alter lymphocyte trafficking, which has been thought to produce its efficacy signal in MS. However, recent work has identified CNS activities that may also contribute to efficacy, which may have particular relevance to reducing neurodegenerative sequelae. The interface between natural product derivatives and endogenous lipid signals may provide new therapeutic avenues for the treatment of MS and perhaps other neurodegenerative conditions.
 

Rapamycin as a Potential Therapeutic for Alzheimer's Disease
Salvatore Oddo, PhD, University of Texas Health Science Center, San Antonio

Accumulation of amyloid-β (Aβ) and tau is an invariant feature of Alzheimer disease (AD). However, the molecular mechanisms linking Aβ and tau accumulation to cognitive decline remain to be elucidated. Here we show that the buildup of Aβ increases the mammalian target of rapamycin (mTOR) signaling, while decreasing mTOR signaling reduces Aβ levels, thereby highlighting an interrelation between mTOR signaling and Aβ. The mTOR pathway plays a central role in controlling protein homeostasis and hence neuronal functions; indeed mTOR signaling regulates different forms of learning and memory. Using rapamycin, a product of the bacterium Streptomyces hygroscopicus and known mTOR inhibitor, we show that restoring mTOR signaling rescues cognitive deficits and ameliorates Aβ and tau pathology in two independent animal models. Mechanistically, the changes in Aβ and tau appear mediated by a rapamycin-mediated increase in autophagy induction. The results presented here provide a molecular basis for the Aβ-induced cognitive deficits and, moreover, show that rapamycin, an FDA approved drug, improves learning and memory and reduces Aβ and tau pathology.
 

Biologically Active Grape-Derived Polyphenols for Targeting Tau Oligomerization and Beta-Amyloidosis
Giulio Maria Pasinetti, MD, PhD, Mount Sinai School of Medicine

Potential development of polyphenols for the prevention or treatment of neurological disorders is largely hindered by their complexity and limited knowledge about bioavailability, metabolism, and bioactivity, especially in the brain. We recently found that polyphenol metabolites characterized in the brain are able to improve cognitive function. We report for the first time that a biosynthetic epicatechin metabolite, 3'-O-methyl-epicatechin-5-O-β-glucuronide (3'-O-Me-EC-Gluc), one of the proanthocyanidin (PAC) metabolites identified in the brain following monomeric treatment, promotes basal synaptic transmission and long-term potentiation at physiologically relevant concentrations in hippocampus slices. PAC has beneficial effects on learning and memory in AD dementia, possibly through mechanisms associated with the prevention of oligomerization of Aβ and abnormal phosphorylation of tau. Our studies suggest select brain-targeted PAC metabolites benefit cognition by improving synaptic plasticity in the brain, and provide impetus to develop 3'-O-Me-EC-Gluc and other brain-targeted PAC metabolites to promote learning and memory in AD and other forms of dementia. Our studies have a major impact by providing vital knowledge on the protective roles of polyphenols in AD.
 

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