Targeting Insulin Resistance for the Treatment of Alzheimer's Disease: From Laboratory to the Clinic

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Targeting Insulin Resistance for the Treatment of Alzheimer's Disease: From Laboratory to the Clinic

Tuesday, April 23, 2013

The New York Academy of Sciences

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Alzheimer's disease (AD) is reaching epidemic levels as the aged population increases. Despite tremendous efforts, no disease-modifying drug is currently available. Mounting epidemiological and basic science evidence links AD and type-2 diabetes mellitus (T2DM). Impairment in insulin receptor transduction pathways affects metabolism of amyloid precursor protein and the balanced phosphorylation of tau protein, two critical players in AD pathology. Furthermore, insulin resistance and dysregulated insulin signaling have been observed in the brains of AD patients. Drugs currently used to treat T2DM improve cognition and brain insulin signaling in rodent AD models, both in vitro and in vivo. Intranasal insulin and two drugs currently used to treat T2DM, metformin and the incretin hormone Exendin-4, a glucagon-like peptide-1 (GLP-1) agonist, are currently in clinical trials for mild cognitive impairment (MCI) and AD. This symposium will highlight the role of insulin resistance in AD, review recent preclinical data supporting the use of antidiabetic drugs to ameliorate AD pathology, and explore the current status of clinical trials using insulin and insulin-sensitizing agents for the treatment of AD.

*Reception to follow.

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Agenda

* Presentation titles and times are subject to change.


Tuesday, April 23, 2013

12:00 PM

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
Cathleen Gonzales, Pfizer Global Research and Development

12:15 PM

Targeting brain insulin resistance as a strategy for treating Alzheimer's disease
Konrad Talbot, PhD, University of Pennsylvania

12:45 PM

Glucose, Insulin, and Amyloid: A Tale of Three (Hippocampal) Molecules
Ewan C. McNay, PhD, University at Albany, SUNY

1:15 PM

Insulin resistance, toxic lipids, inflammation, and stress: The gang of 4 driving neurodegeneration in states of obesity, diabetes, and pathologic aging
Suzanne M. de la Monte, MD, MPH, Brown University

1:45 PM

Coffee break

2:15 PM

Insulin Resistance and Alzheimer's Disease: From Observation to Translation
José A. Luchsinger, MD, MPH, Columbia University Medical Center

2:45 PM

Can tweaking energy metabolism forestall AD?
Mark P. Mattson, PhD, National Institute on Aging, NIH

3:15 PM

Intranasal insulin, deferoxamine and stem cells bypass the blood-brain barrier to treat Alzheimer's, stroke, Parkinson's and other CNS disorders
William H. Frey II, PhD, Alzheimer's Research Center, Regions Hospital, St. Paul, MN

3:45 PM

Questions for all speakers

4:00 PM

Networking reception

5:00 PM

Close

Speakers

Organizers

Mercedes Beyna, MS

Pfizer Global Research and Development

Mercedes Beyna is a research scientist at Pfizer, where she is using biochemical and imaging approaches in the quest to understand the biology underlying various psychiatric disorders. She also performs molecular and cellular biology-based target identification and assay development functions. Captivated by neuroscience, she has worked in the field for over 10 years, in both academic and industrial laboratory settings. Before joining pharmaceutical R&D, Mercedes held lab manager and senior lab technician positions at New York University (NYU). Her experience includes molecular neurobiology, synapse formation and plasticity, neurotrophin signaling, and developmental neurobiology areas. Mercedes attended Binghamton University, earning her undergraduate degree in Biology, and subsequently received her Master's Degree in Biology from NYU. As the Pfizer lead in the Biochemical Pharmacology Discussion Group at the New York Academy of Sciences, she enjoys developing interesting and educational symposia.

Cathleen Gonzales

Pfizer Global Research and Development

Cathleen Gonzales is Principal Scientist in the Neurodegeneration and Neurological Disorders group within the Neuroscience Research Unit located in Cambridge, MA. She has extensive pharmaceutical industry experience primarily in Alzheimer's disease and stroke, leading a preclinical drug discovery team for stroke. Her areas of expertise include in vivo pharmacology and behavioral models of motor dysfunction, memory and cognition. She was the recipient of the 2007 Junior Scientist of the Year Award at Wyeth Pharmaceuticals for her work in the Alzheimer's disease program. Prior to working in industry, she had several years of academic research experience in neuroanatomy and histological techniques with an emphasis on basal ganglia neurobiology.

Barbara Petrack, PhD

Drew University

Barbara Petrack is a RISE Fellow biochemist at Drew University, Madison, NJ, where for 16 years she has mentored students doing research projects. She now collaborates with Roger Knowles, Drew Neurobiologist, in research on Alzheimer's disease. Previously, Barbara was Senior Research Fellow at Novartis, with 35 years in one company (Novartis, CIBA.Geigy, Geigy). She is a NYAS Fellow, has a PhD in Biochemistry from NYU Medical School, followed by a 3-year Post-doc at Rockefeller University in the Laboratory of Fritz Lipmann (Nobel Laureate).

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Suzanne M. de la Monte, MD, MPH

Brown University

Dr. Suzanne M. de la Monte received her undergraduate and medical degrees from Cornell University, and MPH from The Johns Hopkins Bloomberg School of Public Health. She completed an Anatomic Pathology residency at Johns Hopkins Hospital, and Neuropathology fellowship at the Massachusetts General Hospital/Harvard Medical School. She is currently Professor of Pathology (Division of Neuropathology), Neurosurgery, and Neurology, and holds an appointment in the Dept. of Medicine. Her research is mainly focused on mechanisms and consequences of brain insulin resistance in relation to neurodegeneration and development. Her research helped sculpt the concept that Alzheimer's is a form of brain diabetes. Dr. de la Monte also teaches molecular neuroscience, neuropathology, and research methodology, and she serves on a number of academic and advisory committees at Brown, Rhode Island Hospital, and National Institutes of Health.

William H. Frey II, PhD

Alzheimer's Research Center, Regions Hospital, St. Paul, MN

Dr. William H. Frey II is Director of the Alzheimer's Research Center at Regions Hospital in St. Paul, MN, Professor of Pharmaceutics and faculty member in Neurology and Neuroscience at the University of Minnesota and consultant to the pharmaceutical and biotechnology industry. His patents, owned by Novartis, Stanford University, HealthPartners Research Foundation and others, target noninvasive delivery of therapeutic agents, including stem cells, to the brain and spinal cord for treating neurological and psychiatric disorders. Dr. Frey's noninvasive intranasal method for bypassing the blood-brain barrier to target CNS therapeutic agents to the brain while reducing systemic exposure and unwanted side effects has captured the interest of both pharmaceutical companies and neuroscientists. The intranasal insulin treatment he developed for Alzheimer's disease has been shown in clinical trials to improve memory in both Alzheimer's patients and normal adults. With over 100 publications in scientific and medical journals, Dr. Frey has been interviewed on Good Morning America, The Today Show, 20/20, All Things Considered and numerous other shows in the U.S., Europe and Asia. Articles about Dr. Frey's research have appeared in the Wall Street Journal, The New York Times and other magazines and newspapers around the world. Dr. Frey earned his BA in Chemistry at Washington University in 1969 and PhD in Biochemistry at Case Western Reserve University in 1975.

José A. Luchsinger, MD, MPH

Columbia University Medical Center

Jose Luchsinger is an Associate Professor of Medicine and Epidemiology at Columbia University Medical Center. He is the PI of a clinical trial of metformin in Alzheimer's disease prevention and is co-investigators in several studies exploring the relation of insulin resistance with cognition.

Mark P. Mattson, PhD

National Institute on Aging, NIH

After receiving his PhD degree from the University of Iowa, Dr. Mattson completed a postdoctoral fellowship in Developmental Neuroscience at Colorado State University. He then joined the Sanders-Brown Center on Aging and the Department of Anatomy and Neurobiology at the University of Kentucky College of Medicine as an Assistant Professor. Dr. Mattson was promoted to the rank of Associate Professor with tenure and then to Full Professor. In 2000, Dr. Mattson took the position of Chief of the Laboratory of Neurosciences at the National Institute on Aging in Baltimore, where he leads a multi-faceted research team that applies cutting-edge technologies in research aimed at understanding molecular and cellular mechanisms of brain aging and the pathogenesis of neurodegenerative disorders. He is also a Professor in the Department of Neuroscience at Johns Hopkins University School of Medicine where he is the director of a course on the Neurobiology of Aging. Dr. Mattson has received many awards including the Metropolitan Life Foundation Medical Research Award, the Alzheimer's Association Zenith Award, the Jordi Folch Pi Award, the Santiago Grisolia Chair Prize, the Tovi Comet-Walerstein Science Award and several Grass Lectureships. He was elected an AAAS Fellow in 2011. He is Editor-in-Chief of Ageing Research Reviews and NeuroMolecular Medicine and has been/is a Managing or Associate Editor of the Journal of Neuroscience, Trends in Neurosciences, the Journal of Neurochemistry, the Neurobiology of Aging, and the Journal of Neuroscience Research.

Ewan C. McNay, PhD

University at Albany, SUNY

Ewan McNay holds appointments in Behavioral Neuroscience and Biology at SUNY Albany, and an adjunct appointment in Endocrinology at Yale. His work focuses on metabolic regulation of cognitive processes, largely focused on hippocampal function and with an emphasis on disease states that cause brain metabolic dysregulation, such as type 2 diabetes and Alzheimer's disease. Dr. McNay's work began with investigation of the mechanisms by which glucose acts to enhance hippocampal function, which improved understanding of brain glucose supply and demand, and has recently included demonstration of a key role for endogenous insulin signaling in hippocampal mnemonic processing; additional recent work has looked at the molecular impact of both insulin and beta-amyloid within the hippocampus, and at the interaction between these two proteins.

Konrad Talbot, PhD

University of Pennsylvania

Dr. Konrad Talbot received his PhD in behavioral neuroscience from UCLA in 1989. After teaching that subject as an assistant professor at Mount St. Mary's College in California (1990-1995) and St. Olaf College in Minnesota (1995–1997), he pursued a different career as a postmortem Alzheimer's disease (AD) investigator. This began with a postdoctoral fellowship in the Department of Pathology and Laboratory Medicine at the University of Pennsylvania (Penn, 1997–2001) and continued at the same university with appointments as a senior research investigator (2001–2007) and subsequently a research assistant professor in the Department of Psychiatry. In that department, Dr. Talbot has helped identify novel molecular pathologies contributing to cognitive deficits in both schizophrenia and AD. The latter are most relevant here. Working with experts in AD (Dr. John Trojanowski) and diabetes (Dr. Bryan Wolf) at Penn, Dr. Talbot sought the molecular basis for connections between those disorders initially suggested by epidemiological studies. In 2003, he discovered postmortem immunohistochemical evidence that the brain in AD was insulin resistant even in the absence of diabetes, for which he received a T.L.L. Temple Foundation Discovery Award from the Alzheimer's Association. Using a novel ex vivo stimulation paradigm, Dr. Talbot and Dr. Hoau-Yan Wang at CUNY have now provided the first direct demonstration of brain insulin (and IGF-1) resistance in AD and shown its likely molecular causes and cognitive effects (J. Clin. Invest. 122: 1316-1338, 2012). Working with Dr. Wang and Dr. Christian Hölscher at Ulster University, Dr. Talbot's group focuses increasingly on translational studies given its finding that brain insulin resistance is greatly reduced with the FDA-approved antidiabetic liraglutide (Victoza).

Sponsors

Grant Support

This activity is supported by an educational donation provided by Amgen.

Promotional Partners

Alzheimer Research Forum

American Academy of Neurology

American Neurological Association

The Dana Foundation

The Journal of Clinical Investigation

Nature

The New York Academy of Medicine

Society for Neuroscience


The Biochemical Pharmacology Discussion Group is proudly supported by




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

Abstracts

Targeting Brain Insulin Resistance as a Strategy for Treating Alzheimer's Disease
Konrad Talbot, PhD, University of Pennsylvania

It has now been shown that the brain in Alzheimer's disease (AD) is insulin resistant, a condition capable of triggering or exacerbating the pathophysiology of the disorder and its cognitive symptoms. Recent studies have also shown that these features of AD can be reduced by intranasal insulin and/or by peripheral administration of insulin sensitizers known as glucagon-like peptide 1 (GLP-1) analogues. This talk explains the evidence for brain insulin resistance in AD, its proximal causes, cognitive consequences, and amelioration by GLP-1 analogues. In particular, evidence will be presented (a) that the cerebral cortex and hippocampus are insulin resistant in AD, (b) that such resistance is due to beta amyloid (Aβ) suppression of insulin receptor substrate 1 (IRS-1), (c) that markers of IRS-1 suppression are highly associated with cognitive decline, and (d) that GLP-1 analogues approved for use in the U.S. and the EU can elevate brain insulin functions, reduce neuropathology, and may raise cognition in AD. Such findings suggest that treating brain insulin resistance in AD is now a clinical possibility and could be a safe and effective strategy for treating this disorder.
 

Glucose, Insulin, and Amyloid: A Tale of Three (Hippocampal) Molecules
Ewan C. McNay, PhD, University at Albany, SUNY

The hippocampus is well-established to be critically sensitive to glucose supply and metabolism; disease states that impair this (including, for example, type 2 diabetes and Alzheimer's disease) cause cognitive impairment that correlates with the reduction in metabolism. Central to those disease states are specific molecular regulators of hippocampal glucose use: the proteins insulin and beta-amyloid. It turns out that these two proteins interact and oppose in several ways. In this talk I'll look at some of our recent data on modulation of cognitive function and hippocampal metabolism, and suggest some molecular points of interaction between these regulators (specifically, the insulin-sensitive glucose transporter GluT4) that may give insight into both the impact of disease states and potential therapeutic approaches.
 

Insulin Resistance, Toxic Lipids, Inflammation, and Stress: The Gang of 4 Driving Neurodegeneration in States of Obesity, Diabetes, and Pathologic Aging
Suzanne M. de la Monte, MD, MPH, Brown University

The brain requires intact insulin and insulin like growth factor (IGF) signaling for metabolic homeostasis, neuronal plasticity, and myelin maintenance. Insulin and IGF resistance and deficiency disrupt energy balance and signaling networks needed for a broad range of functions, including cell survival. In Alzheimer's disease (AD), cognitive impairment and neurodegeneration are associated with insulin and IGF resistance and reduced signaling through pro-growth and pro-survival pathways. Furthermore, the sharply increased prevalence rates of AD overlap with trends for other insulin resistance diseases, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, and metabolic syndrome, such that their occurrences now frequently co-occur, whereas previously they did not. These findings led to the concept that AD might be caused or worsened by peripheral insulin resistance diseases, including obesity or diabetic states. Still, this notion must be reconciled with the fact that AD is largely driven by aging and selective impairments in insulin/IGF actions in the brain. The questions to be addressed are: 1) How do peripheral insulin resistance diseases contribute to the pathogenesis of cognitive impairment and neurodegeneration? And 2) Do similar pathogenic factors mediate AD, whether or not peripheral insulin resistance diseases, or specific genes abnormalities or variants exist? Evidence suggests that these themes are linked by the eventual dysregulation of lipid metabolism that results in accumulation of cytotoxic lipids, particularly ceramides. Toxic lipids promote inflammation, oxidative stress, ER stress, and insulin resistance, and they can traffic through peripheral blood and cross the blood–brain barrier. To explain how peripheral insulin resistance diseases can initiate or exacerbate cognitive impairment and neurodegeneration, we propose that toxic ceramides generated in liver or visceral fat, leach into peripheral blood due local cellular injury or death. The toxic ceramides cross the blood–brain barrier, and either initiate or facilitate a neurodegeneration cascade mediated by insulin resistance, inflammation, stress, and cell death (extrinsic pathway). In AD-only or AD-predominant cases, insulin/IGF resistance develop mainly in the brain, and the local production of toxic lipids, e.g. ceramides, establishes a positive feedback mal-signaling loop driven by inflammation, stress, and insulin resistance (intrinsic pathway). With regard to sporadic disease, efforts should be made to identify environmental and exposure factors that drive pathological brain aging, since experimental models and epidemiological studies indicate roles for nitrosamine and tobacco exposures. Finally, familial forms of AD fit into the proposed paradigm because the gene mutations (AβPP, PS1, and PS2) or variants (ApoE-ε4) that either cause or increase risk for AD, prematurely disrupt brain insulin/IGF signaling networks. These concepts help delineate the multi-pronged strategies needed to detect, monitor, treat, and prevent AD, together with other major insulin resistance diseases.
 

Insulin Resistance and Alzheimer's Disease: From Observation to Translation
José A. Luchsinger, MD, MPH, Columbia University Medical Center

Insulin resistance and its related conditions, obesity and diabetes, are related to higher risk of Alzheimer's disease in observational studies. These observations are alarming because the majority of the United States adult population have insulin resistance. However, these observations also present an opportunity for the prevention of Alzheimer's disease given that there are known strategies to treat insulin resistance. This presentation will describe the evidence from observational studies and present examples of translation to treatment and prevention strategies.
 

Can Tweaking Energy Metabolism Forestall AD?
Mark P. Mattson, PhD, National Institute on Aging, NIH

Two factors that profoundly affect the risk for metabolic syndrome and poor brain health, particularly in the contexts of ageing and Alzheimer's disease (AD), are energy intake and exercise. Our research in animal models has demonstrated that dietary energy restriction, particularly intermittent fasting, can protect neurons against dysfunction and degeneration in experimental models of AD, Parkinson's disease (PD) and stroke. Energy restriction activates adaptive cellular stress response signaling pathways in neurons resulting in the production of neurotrophic factors, protein chaperones, DNA repair enzymes and proteins critical for mitochondrial biogenesis. Among these factors, brain-derived neurotrophic factor (BDNF) appears to be particularly important in enhancing synaptic plasticity, neurogenesis and cognitive performance. Excessive energy intake, particularly in combination with a sedentary lifestyle (an increasingly common scenario in modern societies), reduces the activation of adaptive cellular stress response pathways thereby rendering neurons vulnerable to dysfunction and degeneration. A society-wide effort will be required to optimize and implement diet and lifestyle prescriptions that protect against AD (see Cell Metab. 2012; 16(6):706-722). In addition, the cellular signaling and metabolic pathways modified by energy intake and exercise provide targets for pharmacological interventions; examples from our studies of AD animal models include the GLP-1 analog Exendin-4, nicotinamide, diazoxide and a ketone ester.
 

Intranasal Insulin, Deferoxamine and Stem Cells Bypass the Blood-brain Barrier to Treat Alzheimer's, Stroke, Parkinson's and Other CNS Disorders
William H. Frey II, PhD, Alzheimer's Research Center, Regions Hospital, St. Paul, MN

Intranasal delivery provides a noninvasive method of bypassing the blood-brain barrier to deliver therapeutic agents to the brain and spinal cord within minutes. It also eliminates the need for systemic delivery, thereby reducing unwanted systemic side effects. This is possible because of the unique connections that the olfactory and trigeminal nerves provide between the brain and external environment. Small molecules, macromolecules and even stem cells are rapidly delivered intranasally to the brain. Using this delivery, targeting and treatment method, which I first invented in 1989, therapeutic proteins, oligonucleotides and small molecules have been used to treat Alzheimer's, Parkinson's, stroke, brain tumors and other brain disorders in animal models. For example, intranasal deferoxamine improves memory in normal mice, reduces memory loss in Alzheimer's transgenic mice and treats stroke in animal models.
 
The intranasal insulin treatment for Alzheimer's disease, which I patented in 2001, has been shown to improve memory in normal human adults and improve memory, attention and functioning in patients with Alzheimer's disease in multiple phase II clinical trials without altering blood levels of insulin or glucose. The treatment rationale and results of intranasal insulin clinical trials will be discussed. Intranasal insulin may be able to reduce the risk of aging diabetics and others from developing Alzheimer's disease in addition to its use in treating patients who already have Alzheimer's disease. Together with Dr. Lusine Danielyan and colleagues in Germany, we have shown that intranasal therapeutic cells bypass the blood-brain barrier by migrating from the nasal mucosa through the cribriform plate along the olfactory neural pathway into the brain and spinal cord. Using intranasal therapeutic cells in animal models, we have demonstrated improvement in an animal model of Parkinson's disease while others have reported improvement in neonatal ischemia, stroke and MS. Intranasal delivery is changing the way we treat CNS disorders.
 

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