METABOLIC SYNDROME AND NEUROLOGICAL DISORDERS … · metabolic syndrome and neurological disorders edited by tahira farooqui and akhlaq a. farooqui

Heart Disease

Dementia

Stroke

Metabolic Syndrome

Alzheimer Disease

Depression

Parkinson Disease

METABOLIC SYNDROME AND NEUROLOGICAL DISORDERSEdited byTahira Farooqui and Akhlaq A. Farooqui

METABOLIC SYNDROME ANDNEUROLOGICAL DISORDERS

METABOLIC SYNDROME ANDNEUROLOGICAL DISORDERS

Edited by

TAHIRA FAROOQUI AND AKHLAQ A. FAROOQUI

This edition first published 2013 C© 2013 by John Wiley & Sons, Inc.

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Metabolic syndrome and neurological disorders / Tahira Farooqui and Akhlaq A. Farooqui, editors.p. ; cm.

Includes bibliographical references and index.ISBN 978-1-118-39527-1 (cloth : alk. paper) – ISBN 978-1-118-39528-8 (Epub) – ISBN 978-1-118-39529-5 (Epdf) –

ISBN 978-1-118-39530-1 (Emobi) – ISBN 978-1-118-39531-8 (ebook)I. Farooqui, Tahira, editor of compilation. II. Farooqui, Akhlaq A., editor of compilation.[DNLM: 1. Metabolic Syndrome X–etiology. 2. Metabolic Syndrome X–metabolism. 3. Nervous System Diseases–etiology.

4. Nervous System Diseases–metabolism. WK 820]RC629616.3′99–dc23

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CONTENTS

Foreword xiMark P. Mattson

Preface xiiiTahira Farooqui and Akhlaq A. Farooqui

Acknowledgments xvTahira Farooqui and Akhlaq A. Farooqui

Contributors xvii

1 Insulin Resistance and Metabolic Failure Underlie Alzheimer Disease 1Suzanne M. de la Monte and Ming Tong

2 Insulin Receptor and the Pathophysiology of Alzheimer Disease 31Johanna Zemva and Markus Schubert

3 Contribution of Insulin Resistance in Pathogenesis of Alzheimer Disease 51Adnan Erol

4 Insulin–Leptin Signaling in the Brain 75Vicente Barrios, Emma Burgos-Ramos, and Jesus Argente

5 The Janus Face of Insulin in Brain 85Ana Duarte, Emanuel Candeias, Sonia C. Correia, Renato X. Santos, Cristina Carvalho,Susana Cardoso, Ana I. Placido, Maria S. Santos, Catarina R. Oliveira, and Paula I. Moreira

6 Modulation of Cognition by Insulin and Aging: Implications for Alzheimer Disease 115Maite Solas and Maria J. Ramırez

vii

viii CONTENTS

7 Contribution of Phospholipid, Sphingolipids, and Cholesterol-Derived Lipid Mediators inthe Pathogenesis of Metabolic Syndrome and Neurological Disorders 137Akhlaq A. Farooqui and Tahira Farooqui

8 Lipids, Cholesterol, and Oxidized Cholesterol in Alzheimer Amyloid Beta-MediatedNeurotoxicity 163Mun’delanji C. Vestergaard, Masamune Morita, Tsutomu Hamada, and Masahiro Takagi

9 Of Sound Mind and Body: Dietary Lifestyles, Promotion of Healthy Brain Aging, andPrevention of Dementia in Healthy Individuals 179Giulio Maria Pasinetti, Amanda Bilski, Lap Ho, Jun Wang, Mario Ferruzzi, Masahito Yamada,Kenjiro Ono, and Salvatore Mannino

10 Metabolic Syndrome as an Independent Risk Factor of Silent Brain Infarction 191Jae-Sung Lim and Hyung-Min Kwon

11 Neurochemical Linkage Among Metabolic Syndrome, Alzheimer Disease, and Depression 197Undurti N. Das

12 Alterations in the Endocannabinoid System as a Link Between Unbalanced EnergyHomeostasis, Neuroinflammation, and Neurological and Neuropsychiatric Disorders 219Tiziana Bisogno and Vincenzo Di Marzo

13 Metabolic Syndrome, Alzheimer Disease, Schizophrenia, and Depression: Role for Leptin,Melatonin, Kynurenine Pathways, and Neuropeptides 235George Anderson and Michael Maes

14 Binge Eating and Metabolic Syndrome 249Ignacio Jauregui-Lobera

15 Phytochemical Principles in the Traditional Indian System of Medicine Used for theManagement of Metabolic Syndrome 261Syed Ibrahim Rizvi and Neetu Mishra

16 Oxidative Stress and Obesity: Their Impact on Metabolic Syndrome 275Morihiro Matsuda and Iichiro Shimomura

17 The Relationship Among Obesity, Inflammation, and Insulin Resistance 283Jean-Philippe Bastard and Bruno Feve

18 Involvement of Adipocytokines in Pathogenesis of Insulin Resistance, Obesity,and Metabolic Syndrome 297Hardik Gandhi and Ramachandran Balaraman

19 Obesity, Inflammation, and Vascular Disease: Novel Insight in the Role of Adipose Tissue 311Paolo Calabro, Enrica Golia, Valeria Maddaloni, Giuseppe Limongelli, Brunella Ziello, Fabio Fimiani,Ilaria Jane Romano, Mario Crisci, Maria Giovanna Russo, Edward T.H. Yeh, and Raffaele Calabro

CONTENTS ix

20 Is Diabetes a Risk Factor for Parkinson Disease? 327Akhlaq A. Farooqui and Tahira Farooqui

21 Role of Iron in the Pathogenesis of Diabetes and Metabolic Syndrome 335Lu Cai

22 Contributions of AMP Kinase to the Pathogenesis of Type 2 Diabetes andNeurodegenerative Diseases 363Mohamed Kodiha, Hicham Mahboubi, and Ursula Stochaj

23 A� Deposition, Insulin Signaling, and Tau Phosphorylation in Animal Models ofAlzheimer Disease and Diabetes 383Naoyuki Sato and Ryuichi Morishita

24 In Vivo Evidence of the Convergence of Type 2 Diabetes and Alzheimer Disease 395Sun Ah Park

25 Metabolic Syndrome and its Impact on Cardiovascular Disease 409John A. Larry

26 Contribution of Inflammation, Adiponectin, and Obesity in Cardiovascular Diseases 423Harald Mangge and Gunter Almer

27 Brain and Cardiovascular Diseases: Molecular Aspects 439Ewa Szczepanska-Sadowska

28 Molecular Aspects of Dietary–Exercise Regimen for the Prevention of Metabolic Syndrome 461Wataru Aoi

29 Ghrelin, Lipid Metabolism, and Metabolic Syndrome 475Pablo B. Martınez de Morentin, Sulay Tovar, Ruben Nogueiras, Miguel Lopez, and Carlos Dieguez

30 Leptin and Cognitive Function 485Jenni Harvey

31 Fructose, Sugar Consumption, and Metabolic Diseases 501Virgile Lecoultre and Luc Tappy

32 Inflammation-Mediated Cognitive and Emotional Alterations in Experimental Modelsof Metabolic Syndrome 515Nathalie Castanon and Sophie Laye

33 Summary and Perspective 529Tahira Farooqui and Akhlaq A. Farooqui

Index 539

Color plate section is located between pages 196 and 197.

FOREWORD

Metabolic syndrome (MetS) is a pathologic state thatmost often results from a chronic positive energy bal-ance due to an excessive energy intake (particularlyrefined sugars and saturated and trans fats) and asedentary lifestyle. The defining clinical features ofMetS are insulin resistance, central obesity, dyslipi-demia, and hypertension. It was established severaldecades ago that MetS is prodromal to diabetes andthat individuals with MetS have a high risk of myocar-dial infarction and stroke. However, within the pastten years it has become clear that MetS adverselyaffects brain structure and function and is a risk factorfor Alzheimer disease (AD) and stroke. In MetabolicSyndrome and Neurological Disorders Tahira andAkhlaq Farooqui have drawn upon the knowledgeof experts in the fields of neuroscience, neurology,endocrinology, cardiovascular disease, obesity, anddiabetes to compile a timely review of the impactof MetS on the brain and its vulnerability to neuro-logical disorders. This is a critically important areaof research for four major reasons: (1) there is anongoing epidemic of overweight, obesity, and MetSin modern societies; (2) due to advances in the earlydiagnosis and treatment of cancers and cardiovascu-lar disease, large numbers of individuals are reach-ing their seventh, eighth, and ninth decades of life,the “danger zones” for AD and stroke; (3) there areno effective drugs to counteract the neuronal damage

that occurs in AD and stroke; and (4) AD patients andstroke patients often require a decade or more of con-stant care, and therefore place a greater personal andeconomic burden on society than many other majordiseases. Although less profound, emerging evidencealso suggests that, in addition to AD and stroke, theMetS may predispose to a broader range of neurolog-ical disorders including Parkinson disease, depres-sion, and possibly schizophrenia.

Because of its adverse effects on essentially allorgan systems including the brain, an understandingof the molecular and cellular alterations that cause theMetS, and the mechanisms by which the MetS pro-motes dysfunction and degeneration of brain cells,will be required to develop novel approaches forpreventing and treating MS and associated diseases.As detailed in Metabolic Syndrome and Neurolog-ical Disorders, alterations resulting from a chronicpositive energy balance that are involved in the gen-esis of the MetS include oxidative stress and inflam-mation and associated dysregulation of lipid (sph-ingolipids, cholesterol, and others) metabolism. Asa result, signaling pathways that normally protectbrain cells and promote their optimal functionality areimpaired, including pathways activated by the hor-mones insulin, leptin, adiponectin, and brain-derivedneurotrophic factor (BDNF). In addition, oxidativestress, inflammation, and abnormal lipid metabolism

xi

xii FOREWORD

can increase the production and/or reduce the removalof the neurotoxic amyloid beta-peptide, which likelycontributes to the dysfunction and degeneration ofneurons in AD. With regards to the pathogenesis ofstroke, hypertension, dyslipidemia, and local oxida-tive stress and inflammation in cerebral blood vesselsresult in a narrowing and weakening of the vessels.

The good news for those with motivation isthat the MetS can be effectively prevented andtreated by adherence to prescriptions for exerciseand dietary energy restriction. Exercise and energyrestriction (particularly intermittent fasting) can pre-vent or reverse MetS by enhancing insulin sensitiv-ity, increasing utilization of fats, stimulating antioxi-dant and anti-inflammatory pathways, and enhancingparasympathetic tone, which decreases blood pres-sure. Recent findings from animal research, and epi-demiological and clinical studies, suggest that ADand stroke may also be prevented or delayed by reg-ular exercise and moderation in energy intake dur-ing adult life. In addition to protecting the brainby reversing all of the peripheral manifestations ofthe MetS, exercise and energy restriction have beenshown to have direct effects on brain cells that opti-mize brain function and may forestall AD and stroke.These include increased production of neurotrophicfactors, improved cellular bioenergetics, and reducedoxidative stress.

For those unwilling or unable to exercise regularlyand restrict their calorie intake so as to maintain a

normal body weight Metabolic Syndrome and Neuro-logical Disorders reviews potential dietary and druginterventions that are being developed and tested inclinical studies. As with research toward understand-ing disease mechanisms, translational research forMetS and neurodegenerative disorders is acceleratedby the use of animal models. Studies of animal modelsof AD and stroke have demonstrated beneficial effectsof insulin, leptin, incretin peptides such as glucagon-like peptide 1 analogs, and PPAR-� agonists thatare insulin-sensitizing agents such as metformin androsiglitazone. Many of these drugs are now in clinicaltrials in patients with mild cognitive impairment orearly AD. Targeting lipid metabolism is also beingpursued via studies of dietary supplementation withomega-3 fatty acids or the use of cholesterol-loweringdrugs. Other approaches that might prove beneficialfor protecting the brain in subjects with MetS includedrugs that suppress appetite, such as cannabinoidreceptor antagonists. This book will provide a valu-able resource to guide future research projects to dis-entangle the complex cellular and molecular under-pinnings of MetS-related neuropathologies, and tothereby inform the development of novel therapeuticinterventions for neurological disorders.

MARK P. MATTSON

National Institute on AgingIntramural Research Program

Baltimore, MD

PREFACE

At the end of 2011, the United Nations declaredfor the first time in the history of human-ity that non-communicable diseases had outpacedinfectious diseases as the main global threat tohuman health. Among non-communicable diseases,metabolic syndrome (MetS), cardiovascular diseases,and Alzheimer disease (AD) are of paramount impor-tance. MetS is a condition characterized by clusteringof insulin resistance, hyperinsulinemia, hypertension,dyslipidemia, impaired glucose disposal, type 2 dia-betes, abnormal blood fat levels, fatty liver disease,and abdominal obesity. Changes in human dietaryhabits in recent decades have led to the consumptionof hypercaloric diets that are rich in saturated fatsand simple sugars (sucrose, glucose, and fructose).The MetS is a highly prevalent pathological conditionthat affects a considerate number of adult humans.Approximately one-fourth of European, American,and Canadian adults suffer from MetS. Clusteringof insulin resistance, hyperinsulinemia, hyperten-sion, dyslipidemia, impaired glucose disposal, type2 diabetes, and abdominal obesity reflects over-nutrition, sedentary lifestyles, physical inactivity, andresultant excess adiposity. At the molecular level,MetS is accompanied not only by dysregulation inthe expression of adipocytokines and chemokines,but also by increase in levels of lipids and lipidmediators (free fatty acids, di- and triacylglycerols,

and ceramide). These changes modulate immuneresponse and inflammation that lead to alterationsin the hypothalamic body-weight/appetite/satiety setpoint, resulting in the initiation and developmentof MetS.

MetS is a risk factor for neurological disorderssuch as stroke, depression, and AD. The molecu-lar mechanism underlying the relationship betweenMetS and neurological disorders is not fully under-stood. However, major mechanisms through whichMetS may influence stroke, AD, and depressioninclude insulin resistance, impairment in insulinreceptor, and insulin growth factor signaling, glu-cose toxicity, elevated levels of phospholipid-,sphingolipid-, and cholesterol-derived lipid media-tors, generation of advanced glycation endproducts,activation of receptor for advanced glycation end-products, cerebrovascular injury, and vascular inflam-mation that may represent a pathological bridgebetween MetS and neurological disorders such asstroke, AD, and depression.

Information on molecular links between MetS andneurological disorders is scattered throughout the lit-erature mainly in the form of original papers andsome reviews. Although, many books are publishedon biochemistry of MetS and neurological disordersseparately, at present there are no books on the rela-tionship between MetS and neurological disorders.

xiii

xiv PREFACE

As the Baby Boomer generation grows older, enor-mous impact of MetS on neurological disorders willbe felt by American society. The projected cost toMedicare for treating stroke, Alzheimer disease, anddepression is estimated to be about 5 trillion dollarsby 2050. This number does not include other visceraland neurological diseases, or various types of can-cers. Such an amount will not only burst NIH budget,but also will seriously affect US economy. Althoughavailable drugs may not reverse the stroke, AD, anddepression, healthy diet, regular exercise, and retar-dation of MetS may produce beneficial effects notonly on motor and cognitive functions, but also onmemory deficits that occur to some extent duringnormal aging and to a large extent in stroke, AD, anddepression. This edited book provides readers witha comprehensive and cutting-edge description of thelinks among MetS, stroke, AD, and depression in amanner that is useful not only to students and teachersbut also to researchers, dietitians, nutritionists, andphysicians.

This edited book presents research activitiesrelated to MetS and neurological disorders from16 countries within 33 chapters. Chapters 1–6 aredevoted to insulin signaling in the brain and its impli-cations on aging and neurological disorders. Chap-ters 7 and 8 are focused on cutting-edge informationon the contribution of lipid and cholesterol-derivedmediators in the pathogenesis of MetS and neurolog-ical disorders. Chapters 9–15 provide information onthe effect of dietary lifestyle on MetS and neurolog-ical disorders. Chapters 16–19 discuss the biochem-ical impact of oxidative stress and obesity on MetS.Chapters 20–24 deal with the relationship betweendiabetes and neurodegenerative diseases. Chapters 25

and 26 describe MetS and its impact on heart dis-ease. Chapter 27 explores a perspective on molec-ular aspects of brain and cardiovascular diseases.Chapter 28 discusses molecular aspects of dietary–exercise regimen in prevention of MetS. Chapters 29–31 address the contribution of two hormones (Leptinand Ghrelin) that have a major influence on energybalance and sugar consumption in metabolic diseases.Chapter 32 elegantly reviews inflammation-mediatedcognitive and emotional alterations in experimentalmodels of MetS. Finally, Chapter 33 provides readerswith an in-depth perspective on current progress thatwill be important for future research work to under-stand the relationship between MetS and neurologicaldisorders.

We have tried to ensure uniformity and mode ofpresentation as well as a logical progression fromone topic to another and have provided extensive bib-liographies. For the sake of simplicity and unifor-mity, a large number of figures with chemical struc-tures of drugs used for the treatment of metabolicsyndrome and neurological disorders along with linediagrams of colored signal transduction pathways areincluded. We hope that our attempt to integrate andconsolidate the knowledge on metabolic links amongMetS, stroke, Alzheimer disease, and depression willinitiate more studies on molecular mechanisms thatlink metabolic syndrome with neurological disorders.This knowledge may be useful in developing treat-ments of MetS-mediated neurological disorders.

TAHIRA FAROOQUI

AKHLAQ A. FAROOQUI

Columbus, OH

ACKNOWLEDGMENTS

We thank all the authors of this book who shared theirexpertise by contributing chapters of a high standard,thus making our editorial task easier. We are gratefulfor the cooperation and patience of Justin Jeffryes,Executive Editor at Wiley-Blackwell Publishing, forthe professional handling of the manuscript. We arealso thankful to Stephanie Dollan for suggestions andrecommendations during compilation of this book

and our Project Manager Shikha Sharma for manag-ing the proof trafficking and maintaining the qualityof this book. This book would not have been possi-ble without the help and patience of our authors andpublisher.

TAHIRA FAROOQUI

AKHLAQ A. FAROOQUI

xv

CONTRIBUTORS

Adnan Erol, Internal Medicine, Erol Project Devel-opment House for the Disorders of EnergyMetabolism, Silivri-Istanbul, Turkey

Akhlaq A. Farooqui, Department of Molecular andCellular Biochemistry, The Ohio State University,Columbus, OH, USA

Amanda Bilski, Department of Neurology, MountSinai School of Medicine, New York, NY, USA

Ana I. Duarte, Center for Neuroscience and CellBiology, University of Coimbra, 3004-517 Coim-bra, Portugal

Ana I. Placido, Center for Neuroscience andCell Biology, University of Coimbra, 3004-517Coimbra, Portugal and Faculty of Medicine,University of Coimbra, 3000-548 Coimbra,Portugal

Brunella Ziello, Division of Cardiology, Second Uni-versity of Naples, Naples, Italy

Bruno Feve, Institut des maladies cardiometa-boliques et de la nutrition (IHU ICAN), INSERM,UPMC, UMR_S938, Faculte de Medecine Pierreet Marie Curie, site Saint-Antoine, France andService d’Endocrinologie–Metabolisme, HopitalSaint-Antoine, Paris, France

Catarina R. Oliveira, Center for Neuroscience andCell Biology, University of Coimbra, 3004-517Coimbra, Portugal and Laboratory of Biochem-istry, Faculty of Medicine, University of Coimbra,3000-548 Coimbra, Portugal

Cristina Carvalho, Center for Neuroscience andCell Biology, University of Coimbra, 3004-517Coimbra, Portugal and Life Sciences Depart-ment, University of Coimbra, 3001-401 Coimbra,Portugal

Edward T.H. Yeh, Division of Cardiology, SecondUniversity of Naples, Naples, Italy

Emanuel Candeias, Center for Neuroscience andCell Biology, University of Coimbra, 3004-517Coimbra, Portugal

Emma Burgos-Ramos, Department of Endocrinol-ogy, Hospital Infantil Universitario Nino Jesus,Instituto de Investigacion La Princesa, Madrid,Spain

Enrica Golia, Division of Cardiology, Second Uni-versity of Naples, Naples, Italy

Ewa Szczepanska-Sadowska, The Medical Univer-sity of Warsaw, Department of Experimental andClinical Physiology, Warsaw, Poland

xvii

xviii CONTRIBUTORS

Fabio Fimiani, Division of Cardiology, Second Uni-versity of Naples, Naples, Italy

George Anderson, CRC, Glasgow, Scotland

Giulio Maria Pasinetti, Department of Neurology,Mount Sinai School of Medicine, New York, NY,USA; GRECC, James J. Peters Veterans AffairsMedical Center, Bronx, NY, USA

Giuseppe Limongelli, Division of Cardiology, Sec-ond University of Naples, Naples, Italy

Gunter Almer, Research Unit on Lifestyle andInflammation-associated Risk Biomarkers, Clini-cal Institute of Medical and Chemical LaboratoryDiagnosis, Graz, Austria

Harald Mangge, Research Unit on Lifestyle andInflammation-Associated Risk Biomarkers, Clini-cal Institute of Medical and Chemical LaboratoryDiagnosis, Graz, Austria

Hardik Gandhi, Pharmacology Lab, PharmacyDepartment, Faculty of Technology & Engineer-ing, The Maharaja Sayajirao University of Bar-oda, Vadodara, Gujarat, India

Hicham Mahboubi, Department of Physiology,McGill University, Montreal, Canada

Hyung-Min Kwon, Department of Neurology, SeoulNational University Boramae Hospital, Seoul,Republic of Korea

Iichiro Shimomura, Department of MetabolicMedicine, Osaka University Graduate School ofMedicine, Osaka, Japan

Jae-Sung Lim, Department of Neurology, SeoulNational University Boramae Hospital, Seoul,Republic of Korea

Jean-Philippe Bastard, Service de Biochimieet Hormonologie, and Institut des maladiescardiometaboliques et de la nutrition (IHUICAN), INSERM, UPMC, UMR-S938, Facultede Medecine Pierre et Marie Curie, site Saint-Antoine, Service de Biochimie et Hormonologie,Hopital Tenon, France

Jenni Harvey, Division of Neuroscience, MedicalResearch Institute, Ninewells Hospital and Medi-cal School, University of Dundee, Scotland

Jesus Argente, Department of Endocrinology, Hos-pital Infantil Universitario Nino Jesus, Instituto deInvestigacion La Princesa; Department of Pedi-atrics, Universidad Autonoma de Madrid andCentro de Investigacion Biomedica en Red deFisiopatologıa Obesidad y Nutricion (CIBERobn),Instituto de Salud Carlos III, E-28009, Madrid,Spain

Johanna Zemva, Center for Molecular MedicineCologne (CMMC), Center for Endocrinology,Diabetes and Preventive Medicine (CEDP), Uni-versity of Cologne, Cologne, Germany

John A. Larry, Assistant Professor of Medicine,Division of Cardiovascular Medicine, The OhioState University, Wexner Medical Center, Colum-bus, OH, USA

Jun Wang, Department of Neurology, Mount SinaiSchool of Medicine, New York, NY, USA; GRECC,James J. Peters Veterans Affairs Medical Center,Bronx, NY, USA

Lap Ho, Department of Neurology, Mount SinaiSchool of Medicine, New York, NY, USA; GRECC,James J. Peters Veterans Affairs Medical Center,Bronx, NY, USA

Luc Tappy, Department of Physiology, LausanneUniversity School of Biology and Medicine, Lau-sanne, Switzerland

Kenjiro Ono, Department of Neurology and Neuro-biology and Aging, Kanazawa University Grad-uate School of Medical Science, Kanazawa,Japan

Lu Cai, Departments of Pediatrics, RadiationOncology, and Pharmacology and Toxicology,The University of Louisville, Louisville, KY,USA

Maite Solas, Department of Pharmacology andDivision of Neurosciences, CIMA, University ofNavarra, Pamplona, Spain

Maria Giovanna Russo, Division of Cardiology,Second University of Naples, Naples, Italy

Maria J. Ramırez, Department of Pharmacologyand Division of Neurosciences, CIMA, Universityof Navarra, Pamplona, Spain

CONTRIBUTORS xix

Maria S. Santos, Center for Neuroscience and CellBiology, University of Coimbra, 3004-517 Coim-bra, Portugal and Life Sciences Department, Uni-versity of Coimbra, 3001-401 Coimbra, Portugal

Mario Crisci, Division of Cardiology, Second Uni-versity of Naples, Naples, Italy

Mario Ferruzzi, Departments of Nutrition Sci-ence and Food Science, Purdue University, WestLafayette, IN, USA

Mark P. Mattson, Laboratory of Neurosciences,Baltimore, MD, USA

Markus Schubert, Center for Molecular MedicineCologne (CMMC), Center for Endocrinology,Diabetes, and Preventive Medicine (CEDP), Uni-versity of Cologne, Cologne, Germany; Clus-ter of Excellence: Cellular Stress Responsesin Aging-Associated Diseases, University ofCologne, Cologne, Germany; Internal Medicine,SCIVIAS- Hospital St. Josef, Rudesheim am Rhein,Germany

Masahiro Takagi, School of Materials Science,Japan Advanced Institute of Science and Technol-ogy, 1-1 Asahidai, Nomi City, Ishikawa, Japan.

Masahito Yamada, Department of Neurology andNeurobiology and Aging, Kanazawa UniversityGraduate School of Medical Science, Kanazawa,Japan

Masamune Morita, School of Materials Science,Japan Advanced Institute of Science and Technol-ogy, 1-1 Asahidai, Nomi City, Ishikawa, Japan

Michael Maes, Department of Psychiatry Faculty ofMedicine, Pathumwan, Bangkok 10330, Thailand

Miguel Lopez, Department of Physiology, CIMUS,University of Santiago de Compostela-Instituto deInvestigacion Sanitaria, Santiago de Compostela(IDIS) & CIBER Fisiopatologıa de la Obesidad yNutricion (CIBERobn), Spain

Ming Tong, Medicine, Rhode Island Hospital andthe Warren Alpert Medical School of Brown Uni-versity, Providence, RI, USA

Mohamed Kodiha, Department of Physiology,McGill University, Montreal, Canada

Morihiro Matsuda, Laboratory of PreventiveMedicine, Institute of Clinical Research, NationalHospital Organization, Kure Medical Center andChugoku Cancer Center, Hiroshima, Japan

Mun’delanji C. Vestergaard, School of MaterialsScience, Japan Advanced Institute of Science andTechnology, Ishikawa, Japan

Naoyuki Sato, Department of Clinical Gene Ther-apy, and Department of Geriatric Medicine,Osaka University, Graduate School of Medicine,Osaka, Japan

Nathalie Castanon, Laboratory of Nutrition andIntegrative Neurobiology, UMR 1286 INRA, Uni-versity of Bordeaux, Bordeaux, France

Neetu Mishra, Centre of Food Technology, Univer-sity of Allahabad, Allahabad, India

Pablo B. Martınez de Morentin, Department ofPhysiology, CIMUS, University of Santiago deCompostela-Instituto de Investigacion Sanitaria,Santiago de Compostela (IDIS) & CIBER Fisiopa-tologıa de la Obesidad y Nutricion (CIBERobn),Spain

Paolo Calabro, Division of Cardiology, Second Uni-versity of Naples, Naples, Italy

Paula I. Moreira, Center for Neuroscience and CellBiology, University of Coimbra, 3004-517 Coim-bra, Portugal and Laboratory of Physiology, Fac-ulty of Medicine, University of Coimbra, 3000-548Coimbra, Portugal

Ramachandran Balaraman, Pharmacology Lab,Pharmacy Department, Faculty of Technology &Engineering, The Maharaja Sayajirao Universityof Baroda, Vadodara, Gujarat, India

Raffaele Calabro, Division of Cardiology, SecondUniversity of Naples, Naples, Italy

Renato X. Santos, Center for Neuroscience and CellBiology, University of Coimbra, 3001-401 Coim-bra, Portugal and Life Sciences Department, Uni-versity of Coimbra, 3001-401 Coimbra, Portugal

Ryuichi Morishita, Department of Clinical GeneTherapy, Osaka University, Graduate School ofMedicine, Osaka, Japan

xx CONTRIBUTORS

Salvatore Mannino, Geriatric Output Unit,Ospedale Alzano, Bergamo, Italy

Sonia C. Correia, Center for Neuroscience and CellBiology, University of Coimbra, 3004-517 Coim-bra, Portugal and Life Sciences Department, Uni-versity of Coimbra, 3001-401 Coimbra, Portugal

Sophie Laye, Laboratory of Nutrition and Integra-tive Neurobiology, UMR 1286 INRA, University ofBordeaux, Bordeaux, France

Sun Ah Park, Department of Neurology, Soonchun-hyang University College of Medicine, BucheonHospital, Bucheon, Korea

Susana Cardoso, Center for Neuroscience andCell Biology, University of Coimbra, 3004-517Coimbra, Portugal and Life Sciences Depart-ment, University of Coimbra, 3001-401 Coimbra,Portugal

Suzanne M. de la Monte, Departments of Pathology(Neuropathology), Neurology, Neurosurgery, andMedicine, Rhode Island Hospital and the WarrenAlpert Medical School of Brown University, Prov-idence, RI, USA

Syed Ibrahim Rizvi, Department of Biochemistry,University of Allahabad, Allahabad, India

Tahira Farooqui, Department of Molecular and Cel-lular Biochemistry, The Ohio State University,Columbus, OH, USA

Tiziana Bisogno, Endocannabinoid ResearchGroup, Institute of Biomolecular Chemistry,

Consiglio Nazionale delle Ricerche, Pozzuoli(NA), Italy

Tsutomu Hamada, School of Materials Science,Japan Advanced Institute of Science and Technol-ogy, Ishikawa, Japan

Undurti N. Das, UND Life Sciences, Shaker Heights,OH, USA; Jawaharlal Nehru Technological Uni-versity, India; Bio-Science Research Centre, Gay-atri Vidya Parishad College of Engineering, India

Ursula Stochaj, Department of Physiology, McGillUniversity, Montreal, Canada

Valeria Maddaloni, Division of Cardiology, SecondUniversity of Naples, Naples, Italy

Vicente Barrios, Department of Endocrinology,Hospital Infantil Universitario Nino Jesus, Insti-tuto de Investigacion La Princesa, Madrid, Spainand Centro de Investigacion Biomedica en Red deFisiopatologıa Obesidad y Nutricion (CIBERobn),Instituto de Salud Carlos III, E-28009, Madrid,Spain

Vincenzo Di Marzo, Endocannabinoid ResearchGroup, Institute of Biomolecular Chemistry, Con-siglio Nazionale delle Ricerche, Pozzuoli (NA),Italy

Virgile Lecoultre, Department of Physiology, Lau-sanne University School of Biology and Medicine,Lausanne, Switzerland

Wataru Aoi, Kyoto Prefectural University, Kyoto,Japan

1INSULIN RESISTANCE AND METABOLICFAILURE UNDERLIE ALZHEIMER DISEASE

SUZANNE M. DE LA MONTE1–4 AND MING TONG4

1Departments of Pathology (Neuropathology), 2Neurology, 3Neurosurgery, and4Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA

Abstract: Alzheimer disease (AD) is the most common cause of dementia in North America. Despite 30 + years ofintensive research, gaps remain in our understanding of AD pathogenesis and approaches to treatment. However, therecent rapid shift to a paradigm that focuses on the roles of metabolic dysfunction and insulin and insulin-like growthfactor (IGF) resistance as causal agents of cognitive impairment and neurodegeneration holds promise. The overarchinghypothesis, that AD is a brain diabetes (type 3), accounts for the impairments in neuronal survival, myelin maintenance,energy metabolism, synaptic integrity, and plasticity, and the well-recognized neuropathological processes including,tau hyper-phosphorylation, amyloid-beta (APP�-A�) accumulation, oxidative and endoplasmic reticulum stress, andcerebral microvascular disease. Herein, we discuss the roles of aging, lifestyle choices, peripheral insulin resistancediseases, including obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and metabolic syndrome, nitrosamineexposures, and familial/genetic factors as mediators of brain diabetes, cognitive impairment, and neurodegeneration.The data suggest that neurodegeneration can be initiated and propagated by the buildup of agents consequential toperipheral insulin resistance, i.e. toxic lipids (ceramides), and predicts that toxic ceramides generated in liver or visceralfat, cross the blood-brain barrier and cause brain insulin resistance, stress, and inflammation. This extrinsic mechanism ofneurodegeneration accounts for the strikingly concurrent and overlapping increases in prevalence of all insulin resistancediseases. Yet, there is evidence that AD/type 3 diabetes occurs as the dominant or only manifestation of insulin resistance.The predicted intrinsic pathway of neurodegeneration is nearly identical to the extrinsic pathway, except its underlyingbasis is direct toxic/metabolic injury to the brain, or familial AD-associated mutations and gene variants that acceleratethe trajectory to brain insulin resistance with aging. Finally, we propose that progressive cognitive impairment andneurodegeneration in AD are effectuated by a positive feedback mal-signaling cascade, whereby declining function ofinsulin/IGF networks dysregulate lipid metabolism and increase local levels of toxic ceramides. Toxic ceramides promoteinflammation, endoplasmic reticulum and oxidative stress, and mitochondrial dysfunction, all of which exacerbate braininsulin/IGF resistance. Over time and with aging, adducts accumulate in DNA, RNA, protein, and lipids, causing continuousmulti-modal molecular failure, leading to disruption of cytoskeletal function, A�PP-A� secretion, synaptic plasticity, cellsurvival mechanisms, and myelin maintenance. Once established, the reverberating loop must be targeted using multi-pronged approaches to disrupt spiraling progression of the AD neurodegeneration cascade.

Metabolic Syndrome and Neurological Disorders, First Edition. Edited by Tahira Farooqui and Akhlaq A. Farooqui.C© 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

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2 METABOLIC SYNDROME AND NEUROLOGICAL DISORDERS

1.1 INTRODUCTION

The mature brain requires intact insulin and insulin-like growth factor (IGF) signaling for homeostasis,neuronal plasticity, and myelin integrity. Resistanceand deficiency of insulin and IGF disrupt energybalances and signaling networks that are neededto support a broad range of functions, includingcell survival. In recent years, considerable evidencehas accumulated showing that in Alzheimer disease(AD), cognitive impairment and neurodegenerationare associated with insulin and IGF resistance andimpairments in signaling through pro-growth andpro-survival pathways. Furthermore, studies havelinked the sharply increased incidence and preva-lence rates of AD to other chronic insulin resis-tance disease states, including obesity, type 2 dia-betes mellitus, nonalcoholic fatty liver disease, andmetabolic syndrome. On the other hand, there isample evidence that sporadic AD very frequentlyoccurs in the absence of peripheral insulin resis-tance diseases. In addition, because familial formsof AD, although relatively uncommon, have nearlyidentical clinical and neuropathological features assporadic AD, their disease mechanisms ultimatelyshould be shared with those of sporadic AD. Thisreview focuses on two major questions: (1) howdo peripheral insulin resistance diseases contributeto the pathogenesis of cognitive impairment andneurodegeneration; and (2) do the same pathogenicfactors mediate AD neurodegeneration, whether ornot peripheral insulin resistance diseases or muta-tions in the amyloid precursor protein or presenilingenes exist?

These concepts share in common the themeof insulin resistance with dysregulated lipidmetabolism. Consequences include increased localtissue and peripheral blood levels of cytotoxicceramides. Cytotoxic ceramides promote inflamma-tion, oxidative stress, endoplasmic reticulum (ER)stress, and worsened insulin resistance. We proposethat peripheral insulin resistance diseases promote orexacerbate cognitive impairment and neurodegenera-tion by causing brain insulin resistance. Mechanisti-cally, toxic ceramides generated in liver or visceral fatleak into the peripheral circulation due to local cel-lular injury or death. The lipid-soluble nature of thetoxic ceramides enables them to cross the blood-brain

barrier, and either initiate or propagate a cascade ofneurodegeneration mediated by brain insulin resis-tance, inflammation, stress, and cell death (extrinsicpathway).

Human and experimental data indicate that spo-radic AD occurs in the absence of diabetes, obesity,fatty liver disease, or metabolic syndrome. Yet, ADbrains exhibit significant deficits in insulin and IGFsignaling, which worsen as the disease progresses.Clues pertaining to the pathogenesis of disease stemfrom epidemiological and experimental studies. Epi-demiological studies strongly support exposure ratherthan genetic factors as agents of disease. Experi-mental models highlight the role of nitrosamine andrelated toxins as mediators of insulin resistance dis-eases, including in the brain. Mechanistically, wepropose that the nitrosamines (toxins) present in pro-cessed and preserved foods, cause oxidative damage,disrupt lipid metabolism, and impair insulin signal-ing. Toxic lipids (ceramides) accumulated directly inthe brain promote inflammation, stress, and insulinresistance, which together activate a positive feed-back mal-signaling cascade that causes AD-type neu-rodegeneration (intrinsic pathway). Familial forms ofAD are discussed in light of how their gene mutations(A�PP, PS1, and PS2) or variants (ApoE-�4) prema-turely disrupt brain insulin/IGF signaling networks,and thereby accelerate brain aging. These conceptshelp delineate the strategies needed to detect, mon-itor, treat, and prevent AD, as well as other majorinsulin resistance diseases.

1.2 MEDIATORS OF INSULIN SIGNALING

1.2.1 Insulin, the Master Hormone

Insulin is a 5800 Dalton, 51 amino acid polypep-tide, composed of an A (21 residues) chain and B(30 residues) chain linked by disulfide bonds. In theearly 1920s, Banting and Best discovered insulinin pancreatic secretions [1, 2], and shortly there-after demonstrated that it reversed hyperglycemia inhumans [3]. It took nearly 30 years to devise meth-ods that could stabilize insulin, prolong its actions,and delay its absorption, and it took 50 years to pro-duce 99% pure insulin, free of pro-insulin and otherislet polypeptides [4]. Prior to 1980, insulin used totreat humans was extracted from bovine or porcine

INSULIN RESISTANCE AND METABOLIC FAILURE UNDERLIE ALZHEIMER DISEASE 3

pancreas, but early in 1980, commercial sources ofhuman insulin became available.

Advancement of molecular and biochemical tech-nology, including genetic engineering, led to large-scale production of human insulin. Currently, humaninsulin is produced using Saccharomyces cerevisiae(yeast) technology, and insulin is continuously har-vested from the supernatant during fermentation.Insulin is further purified, crystalized, esterified, andhydrolyzed to ensure purity [5]. However, efforts arecurrently underway to produce insulin that can beadministered orally rather than by injection [6].

1.2.2 Insulin-Stimulated Effects

The main targets of insulin include skeletal muscle,adipose tissue, and liver, although virtually everyorgan, tissue, and cell type is responsive to insulinstimulation. Insulin regulates glucose uptake and uti-lization by cells and regulates free fatty acid levels inperipheral blood. Free fatty acids are substrates forgenerating complex lipids. In skeletal muscle, insulinstimulates glucose uptake by inducing translocationof the glucose transporter protein, GLUT4, from theGolgi to the plasma membrane [7]. In liver, insulinstimulates lipogenesis and triglyceride storage, andinhibits gluconeogenesis. In adipose tissue, insulindecreases lipolysis and fatty acid efflux [8]. Thesepro-metabolic effects of insulin on glucose and freefatty acid disposal help to maintain energy balance.

1.2.3 Insulin-Like Growth Factors (IGFs)

Insulin is closely related to another polypeptide,insulin-like growth factor 1 (IGF-1). IGF-1 is alsoreferred to as somatomedin C or mechano growthfactor [9, 10]. IGF-1 regulates growth, particularlyduring development, and it exerts anabolic effects onmature organs and tissues. IGF-1 is composed of 70amino acids (7649 Daltons) in a single chain that con-tains three intra-molecular disulfide bridges [9, 10].IGF-1 is abundantly produced in liver, and its supplyand actions are regulated by interactions with IGFbinding proteins (IGFBPs) [11].

1.2.4 Insulin and IGF Signaling in the Brain

Historically, most of the research concerning insulinand IGF actions focused on cells and tissues other

than those of the central nervous system (CNS).However, within the last 15 to 20 years, informa-tion has steadily emerged about expression and func-tion of insulin and IGF polypeptides and receptorsin the CNS. In the brain, insulin and IGF signalingregulates a broad array of neuronal and glial activ-ities, including growth, survival, metabolism, geneexpression, protein synthesis, cytoskeletal assembly,synapse formation, neurotransmitter function, andplasticity [12, 13]. In addition, insulin and IGF path-ways have critical roles in maintaining cognitivefunction. Insulin, IGF-1, and IGF-2 polypeptide andreceptor genes are expressed in neurons [12] and glialcells [14, 15] throughout the brain, but their highestlevels of expression are in structures that are typi-cally targeted by neurodegenerative diseases [12, 16,17]. The fact that genes encoding insulin, IGFs, andinsulin-like peptides and their receptors are expressedin human, rodent, and drosophila brains [18] suggeststhat the corresponding signaling networks permitlocal control of diverse functions, including energymetabolism.

1.2.5 Insulin and IGF Signal Transduction:Steps in Pathway Activation

The mechanisms of insulin/IGF signaling in thebrain are the same as those in non-CNS cells.Insulin and IGF networks are activated by bind-ing of trophic factors to their own receptors, whichpromotes phosphorylation and activation of intrin-sic receptor tyrosine kinases. Subsequent interac-tions between the tyrosine phosphorylated receptorsand insulin receptor substrate (IRS) proteins medi-ate downstream transmission of signals. Positive sig-naling to inhibit apoptosis and to stimulate growth,survival, metabolism, and plasticity is effectuated byactivating phosphoinositol-3-kinase (PI3K)-Akt andextracellular mitogen-activated protein kinase (ErkMAPK), and by inhibiting glycogen synthase kinase3� (GSK-3�) [17].

1.2.6 Cross Talk between Insulin/IGF andOther Major Signal Transduction Networksin the Brain

Insulin/IGF-1 pathways cross talk with other majornetworks, including Wnt/�-catenin and Notch [19,


20]. Wnt/�-catenin and Notch also support diverseneuronal functions; disruption of these pathways hasbeen implicated in the pathogenesis of neurode-generation [21, 22]. Wnt/�-catenin signaling regu-lates neuronal proliferation, migration, differentia-tion, axon outgrowth, and synaptic plasticity [23–26].In contrast, GSK-3� inhibits Wnt by phospho-rylating �-catenin. This event destabilizes of theAxin/APC/�-catenin complex and targets �-cateninfor ubiquitin/proteasome-mediated degradation [20,27–30]. Notch signaling promotes cell adhesionand remodeling in the CNS, and is activated byinsulin/IGF [31]. Given the breadth of functions sup-ported by insulin/IGF signaling, including its crosstalk with Wnt/�-catenin and Notch, one would log-ically conclude that any significant impairment ininsulin and IGF signaling would have dire conse-quences on the structural and functional integrity ofthe CNS.

1.3 INSULIN RESISTANCEAND NEURODEGENERATION

1.3.1 Insulin Resistance and Its Consequences

Insulin resistance is classically defined as the state inwhich high levels of blood insulin (hyperinsulinemia)are associated with hyperglycemia. The concept hasbroadened to include organ and tissue-related impair-ments in insulin signaling associated with reducedactivation of the pathways. As a result, progressivelyhigher levels of ligand are needed to achieve normalinsulin actions [7]. However, sustained high levels ofinsulin can also cause insulin resistance [32], therebyworsening and possibly broadening tissue involve-ment. Furthermore, hyperinsulinemia impairs insulinsecretion from �-cells in pancreatic islets, yieldinghybrid states of both insulin resistance and insulindeficiency [32].

Long-term consequences of insulin resistanceinclude cellular energy failure (lack of fuel), elevatedplasma lipids, and hypertension. In addition, chronichyperinsulinemia vis-a-vis normoglycemia predictsfuture development of diabetes mellitus [33]. Insulinresistance is an independent predictor of seriousdiseases including cerebrovascular and cardiovascu-lar disease, hypertension, and malignancy [34–38].

Insulin resistance is now front and center stagebecause of its link to our seemingly unbridled obesity,type 2 diabetes mellitus (T2DM), nonalcoholic fattyliver disease (NAFLD), metabolic syndrome, poly-cystic ovarian disease, age-related macular degener-ation, and Alzheimer disease (AD) epidemics.

1.3.2 Alzheimer Disease (AD)

AD Occurrence and Clinical Diagnosis AD is themost common cause of dementia in North Amer-ica. Sporadic AD, which has no clear pattern ofgenetic transmission, accounts for more than 90%of the cases, whereas familial (heritable) forms ofAD account for 5–10% of all cases. Throughoutthe past several decades, sporadic AD has becomeepidemic, raising questions about environmental andlifestyle mediators of cognitive impairment and neu-rodegeneration [39]. Although the clinical diagnosisof AD is based on criteria set by the National Instituteof Neurological and Communicative Disorders andStroke, the Alzheimer Disease and Related Disor-ders Association (NINCDS/ADRDA), and DSM-IVcriteria [40], embracement of additional tools suchas neuroimaging and standardized biomarker pan-els have helped facilitate detection of the early brainmetabolic derangements in AD [41].

AD Neuropathology Neuropathological hallmarksof AD include: neuronal loss; abundant accumula-tions of abnormal, hyper-phosphorylated cytoskeletalproteins in neuronal perikarya and dystrophic fibers;and increased expression and abnormal processingof amyloid-beta precursor protein (A�PP), leadingto A�PP-A� peptide deposition in neurons, plaques,and vessels. The gold standard for definitivelydiagnosing AD is to demonstrate beyond-normalaging associated densities of neurofibrillary tan-gles, neuritic plaques, and A�PP-A� depositsin corticolimbic structures, bearing in mind thatneurodegeneration frequently involves multipleother cortical regions. The common thread amongthese lesions is that they harbor insoluble aggregatesof abnormally phosphorylated and ubiquitinated tau,and neurotoxic A�PP-A� in the form of oligomers,fibrillar aggregates, and plaques. Secreted neurotoxicA�PP-A� oligomers inhibit hippocampal long-term


potentiation, i.e. synaptic plasticity [42], which isneeded for learning and memory.

1.3.3 Concept: AD is a Metabolic DiseaseDriven by Brain Insulin/IGF Resistance

For more than 30 years, research efforts have beensquarely focused on the pathogenic roles of hyper-phosphorylated tau and A�PP-A� in AD. However,growing evidence is highlighting the importance ofinsulin resistance and metabolic dysfunction as medi-ators of AD [43,44]. In essence, AD could be regardedas a metabolic disease tied to and possibly causedby brain insulin and IGF resistance [45, 46]. Cor-respondingly, AD shares many features in commonwith systemic (non-CNS) insulin resistance diseases.For example, reduced insulin-stimulated growth andsurvival signaling, increased oxidative stress, pro-inflammatory cytokine activation, mitochondrial dys-function, and impaired energy metabolism occur inboth AD and peripheral insulin resistance diseases[17, 47, 48]. Even in its early stages, AD is markedby deficits in cerebral glucose utilization [49–51].As AD progresses, brain metabolic derangements[52, 53] and impairments in brain insulin signaling,insulin-responsive gene expression, glucose utiliza-tion, and metabolism worsen [45, 46, 54].

1.3.4 Brain Insulin and IGF Resistance andDeficiency in AD-Human Studies

Human postmortem studies established that braininsulin resistance mediated by reduced insulin recep-tor expression and insulin receptor binding wereconsistent and fundamental abnormalities in AD[45, 46, 54]. Moreover, impairments in signalingare not restricted to insulin pathways as they alsoinvolve IGF-1 and IGF-2 networks [45, 46]. AD-associated deficits in brain insulin and IGF signal-ing progress with disease severity [45] and involvepathways needed to maintain neuronal survival,energy production, gene expression, and plasticity[43]. Correspondingly, nearly all the critical featuresof AD could logically represent consequences ofbrain insulin/IGF resistance. These features includeincreases in (1) activation of kinases that aberrantlyphosphorylate tau and lead to accumulation of neu-rofibrillary tangles, dystrophic neuritic plaques, and

neuropil threads; (2) expression of A�PP and accu-mulation of A�PP-A� peptides that are neurotoxicand result in senile plaque formation; (3) oxidativeand ER stresses, which propagate cell death cascades;(4) mitochondrial dysfunction that causes energydeficits; and (5) disruption of cholinergic home-ostasis needed for neuronal plasticity, memory, andcognition.

1.3.5 AD = Type 3 Diabetes

Unlike systemic forms of diabetes, AD-associateddeficits in insulin/IGF signaling are due to the com-bined effects of insulin/IGF resistance and deficiency.Insulin/IGF resistance is manifested by reduced lev-els of insulin/IGF receptor binding and decreasedresponsiveness to insulin/IGF stimulation, whereasthe trophic factor deficiency is associated withreduced levels of insulin polypeptide and geneexpression in brain and cerebrospinal fluid [44–46].In essence, AD can be regarded as brain diabetes thathas elements of both insulin resistance (T2DM) andinsulin deficiency (T1DM). To consolidate this con-cept, we proposed that AD be referred to as “type 3diabetes” [45, 46].

1.3.6 Experimental Type 3 Diabetes(Sporadic AD)

The hypothesis that AD is actually a brain form of dia-betes is supported by experimental data showing thatintracerebroventricular injection of streptozotocin, apro-diabetes drug, causes rats to develop deficits inspatial learning and memory, along with brain insulinresistance, brain insulin deficiency, and AD-type neu-rodegeneration, but not diabetes mellitus [55,56]. Onthe other hand, intraperitoneal or intravenous admin-istration of streptozotocin causes diabetes mellituswith relatively mild hepatic steatosis and neurode-generation [57,58]. Therefore, brain diabetes (type 3)can occur independent of type 1 or type 2 diabetes,and vice versa.

Further studies utilized small interfering RNAduplex molecules to silence the expression of insulinand IGF receptors in the brain [59] without caus-ing genotoxic and nitrosative damage, which occurwith streptozotocin [57]. The results showed thatdisruption of brain insulin and IGF receptors was


sufficient to cause cognitive impairment and hip-pocampal degeneration with molecular abnormali-ties similar to those in AD [59]. However, it wasalso evident that the oxidative and nitrosative damagewere needed to produce a more robust model. Finally,human and experimental studies demonstrated neu-roprotective effects of glucagon-like peptide-1 (GLP-1) [60], IGF-1 [61], and caloric restriction [62],which respectively stimulate insulin actions, slowbrain aging, and reduce insulin resistance. Together,these studies support the notion that AD is a braindiabetes-type metabolic disease mediated by localinsulin and IGF resistance.

1.4 THE NEUROPATHOLOGYOF AD IS CAUSED BY BRAININSULIN/IGF RESISTANCE

1.4.1 Overview

Chronic insulin/IGF-1 resistance has dire conse-quences on the functional integrity of the brain [12,63] due to impairments in neuronal survival, energyproduction, gene expression, and plasticity [43]. Inhi-bition of insulin/IGF signaling contributes to ADby increasing: (1) the activity of kinases that aber-rantly phosphorylate tau and therefore compromiseneuronal cytoskeletal integrity; (2) the expression ofA�PP and accumulation of A�PP-A�; (3) oxidativestress; (4) endoplasmic reticulum (ER) stress; and(5) metabolic dysfunction with attendant activationof pro-inflammatory and pro-death cascades. Func-tional consequences of brain insulin/IGF resistanceinclude down-regulation of target genes needed forcholinergic homeostasis, and compromise of systemsthat mediate neuronal plasticity, memory, and cogni-tion [43–46].

1.4.2 Tau Pathology

Neurofibrillary tangles, dystrophic neurites, and neu-ropil threads are major neuronal cytoskeletal lesionsthat correlate with dementia in AD [64]. At thecore of these lesions are aggregates of hyperphos-phorylated, ubiquitinated, insoluble fibrillar tau. Tau,a neuronal microtubule-associated protein, becomeshyperphosphorylated due to inappropriate activationof kinases such as GSK-3� [65], cyclin-dependent

kinase 5 (cdk-5), and c-Abl [66], and/or inhibition ofprotein phosphatases 1 and 2A [66, 67]. Hyperphos-phorylation causes tau to misfold, self-aggregate, andform insoluble fibrils (paired helical filaments andstraight filaments) [68] that eventually develop intoneurofibrillary tangles, dystrophic neurites, and neu-ropil threads [67]. Intra-neuronal accumulations offibrillar tau disrupt neuronal cytoskeletal structureand function, impairing axonal transport and synapticintegrity. Synaptic disconnection is one of the hall-marks of AD neurodegeneration [67]. In addition,pre-fibrillar tau can aggregate into neurotoxic solu-ble oligomers or insoluble granular deposits that pro-mote disconnection of synapses and death of neu-rons [69]. Ubiquitination of hyper-phosphorylatedtau [70], together with eventual dysfunction of theubiquitin-proteasome system [71], worsen the accu-mulation of insoluble fibrillar tau. Fibrillar tau exertsits neurotoxic effects by increasing oxidative stress,ROS generation, neuronal apoptosis, mitochondrialdysfunction, and necrosis [72].

Several aspects of the molecular and structuralpathology of tau in AD are explainable on thebasis of brain insulin/IGF resistance [17, 45, 46,73, 74]. First, tau gene expression and phosphoryla-tion are regulated by insulin and IGF [63]. Impair-ments in insulin/IGF signaling contribute to tauhyper-phosphorylation due to over-activation of spe-cific kinases, e.g. GSK-3� and Cdk-5, and impairedtau gene expression [17, 75]. Consequences includefailure to generate sufficient quantities of normalsoluble tau protein, vis-a-vis accumulation of hyper-phosphorylated insoluble fibrillar tau, with atten-dant cytoskeletal collapse, neurite retraction, andsynaptic disconnection. Second, decreased signalingthrough phosphoinositol-3-kinase (PI3K), Akt [63],and Wnt/�-catenin [76], and increased activation ofGSK-3� [65] correlate with brain insulin and IGFresistance. Impairments in signaling through thesepathways could account for the reductions in neuronalsurvival, myelin maintenance, synaptic integrity, neu-ronal plasticity, mitochondrial function, and cellularstress management in AD.

1.4.3 Amyloid-Beta (A�PP-A�)

AD is marked by dysregulated expression and pro-cessing of amyloid precursor protein (A�PP), with


attendant accumulation of A�PP-A� neurotoxicoligomeric fibrils or insoluble larger fibrillar aggre-gates (plaques). Mechanistically, increased A�PPexpression and altered proteolysis lead to accumu-lation of 40 or 42 amino acid A�PP-A� peptides thataggregate. In familial/inherited forms of AD, muta-tions in the A�PP, presenilin 1 (PS1), and PS2 genes,or inheritance of the Apolipoprotein E ε4 (ApoE-ε4) allele, are responsible for increased synthesis anddeposition of A�PP-A� peptides in the brain [77,78].In sporadic AD, which accounts for 90% or more ofthe cases, the cause of A�PP-A� accumulation isstill debated. However, recent evidence suggests thatimpaired insulin/IGF signaling promotes A�PP-A�accumulation due to dysregulated A�PP expressionand protein processing [74].

The concept that A�PP-A� toxicity causes insulinresistance, and the opposing argument, that braininsulin resistance with oxidative stress and neuro-inflammation promote A�PP-A� accumulation andtoxicity, are both supported by experimental data.Studies have shown that insulin stimulation accel-erates trafficking of A�PP-A� from the trans-Golginetwork, where it is generated, to the plasma mem-brane, and that insulin stimulates A�PP-A� extra-cellular secretion [79] and inhibits its intracellularaccumulation and degradation by insulin-degradingenzyme (IDE) [80]. On the other hand, in hyper-insulin states, IDE may become diverted to degradeexcess insulin, leaving A�PP processing deficientand allowing A�PP-A� to accumulate [81]. Whetherthese actions actually contribute to A�PP-A� bur-den is not known. However, it is clear that impairedinsulin signaling can disrupt processing of A�PP andclearance of A�PP-A� [82]. Accumulation of A�PP-A� exacerbates the problem because A�PP-A� dis-rupts insulin signaling by competing with insulin,or reducing the affinity of insulin for binding to itsown receptor [83]. In addition, A�PP-A� oligomersinhibit neuronal transmission of insulin-stimulatedsignals by desensitizing and reducing surface expres-sion of insulin receptors. Furthermore, intracellularA�PP-A� directly interferes with PI3 kinase activa-tion of Akt, which leads to impaired survival sig-naling, increased activation of GSK-3�, and hyper-phosphorylation of tau. Because IGF-1 or IGF-2suppression of GSK-3� [84] reduces the neurotoxiceffects of A�PP [85], the neuro-protective properties

of these and related trophic factors could be exploitedfor treatment of AD.

1.4.4 Oxidative Stress

Chronic insulin/IGF resistance increases both oxida-tive and endoplasmic reticulum (ER) stress [48]. Highlevels of persistent oxidative stress lead to forma-tion of reactive oxygen (ROS) and reactive nitro-gen (RNS) species, which are present in AD brains[86]. ROS and RNS are problematic because theyattack subcellular organelles, including mitochon-dria, and thereby exacerbate oxidative stress. In addi-tion, molecular attacks resulting in stable adductsformed with DNA, RNA, lipids, and proteins, com-promise the structural and functional integrity of neu-rons [87]. Consequences include loss of plasma mem-brane and ER functions, disruption of the neuronalcytoskeleton with dystrophy and synaptic disconnec-tion, deficits in neurotransmitter release and neuronalplasticity, and perturbations of cellular homeostasisand survival mechanisms.

Oxidation of amino acid residues results in for-mation of advanced glycation end products (AGEs)or advanced oxidation protein products. Oxidationcauses proteins to unfold, and renders them inac-tivate and susceptible to cleavage. Oxidation ofaliphatic side-chains produces peroxides and car-bonyls (aldehydes and ketone). Peroxide attack onother molecules generates radicals. Carbonyls aretoxic and cause stress-induced AGE accumulation,which contributes to progressive loss of cellular func-tions in aging, diabetes, human AD, experimentalAD, and other degenerative diseases [88, 89]. There-fore, elevated levels of AGE in A�PP-A� plaquesand neurofibrillary tangles [90–92] may contributeto progressive cell loss with neurodegeneration[87, 90, 92].

1.4.5 Endoplasmic Reticulum Stress

Endoplasmic reticulum (ER) functions, such as pro-tein synthesis, modification, and folding, calcium sig-naling, and lipid biosynthesis, are driven by glucosemetabolism. In insulin resistance states, such as inobesity, T2DM, NASH, and metabolic syndrome,impairments in glucose uptake and utilization are


associated with increased ER stress pathway acti-vation [93–95]. Chronically high levels of ER stresslead to dysregulated lipid metabolism, accumulationof toxic lipids, e.g. ceramides, and activation of pro-inflammatory and pro-apoptosis cascades [96, 16,97]. Recent studies showed that ER stress and dysreg-ulated lipid metabolism occur in human brains withAD, and worsen with severity of disease and progres-sion of brain insulin/IGF resistance [48].

1.4.6 Metabolic Deficits—The Starving Brain

Insulin and IGF signaling regulate glucose utiliza-tion and ATP production in the brain. In AD, deficitsin cerebral glucose utilization and metabolism occurearly and prior to significant cognitive decline [98].Therefore, impairments in brain insulin signalingare probably pivotal to AD pathogenesis [46]. Sup-porting data were provided by experimental ani-mal models in which brain insulin/IGF resistancewas associated with cognitive impairment and AD-type neurodegeneration [55, 99]. Oxidative stress andROS can damage mitochondrial membranes, mak-ing them more permeable, and mitochondrial DNA,impairing electron transport and ATP productionand worsening ROS. Furthermore, oxidative stressand its responses can (1) activate pro-inflammatorynetworks that exacerbate organelle dysfunction andpro-apoptosis mechanisms; (2) stimulate A�PP geneexpression [100] and A�PP cleavage, resulting inincreased formation of A�PP-A� neurotoxic fibrils[85]; and (3) activate or dis-inhibit GSK-3�, whichpromotes tau phosphorylation. Therefore, oxidativestress stemming from brain insulin/IGF resistanceand metabolic dysfunction contribute to neuronalloss, A�PP-A� toxicity, tau cytoskeletal pathology,and neuro-inflammation in AD [12, 45, 101].

Glucose uptake in the brain is mediated bythe GLUT4 transporter [102], which is abundantlyexpressed along with insulin receptors, in the medialtemporal lobe, as well as other notable targets ofAD [12, 17]. Insulin stimulates GLUT4 mRNA,and GLUT4 protein trafficking from the Golgi tothe plasma membrane where it engages in glucoseuptake. In AD, although GLUT4 mRNA expres-sion is preserved [46], deficits in brain glucoseutilization and energy metabolism vis-a-vis brain

insulin/IGF resistance could be mediated by func-tional impairments in GLUT4, i.e. post-translationalmechanisms responsible for GLUT4 trafficking tothe plasma membrane. Resulting deficiencies inenergy metabolism increase oxidative stress [73] andhelp drive pro-apoptosis, pro-inflammatory, and pro-A�PP-A� cascades, which worsen DNA damage,mitochondrial dysfunction, oxidative stress, and ROSgeneration [12, 17, 45, 46, 55].

1.4.7 Chronic Ischemic CerebralMicrovascular Disease

Cerebral microvascular disease is a consistent fea-ture of AD, and recognized mediator of cognitiveimpairment. Postmortem studies demonstrated sim-ilar degrees of dementia in people who had severeAD versus moderate AD plus chronic ischemicencephalopathy. The ischemic injury mainly con-sisted of multifocal small infarcts and leukoaraio-sis, i.e. extensive white matter fiber attrition withpallor or myelin staining [103]. T2DM and hyper-tension are known causes of microvascular diseasethroughout the body, including the brain. Evidencethat microvascular disease contributes to neurodegen-eration was suggested by the finding of progressivemedial temporal lobe atrophy with advancement ofT2DM [104].

Hyperinsulinemia, as occurs with insulin resis-tance in T2DM, causes progressive injury tomicrovessels, ultimately producing a state ofchronic cerebral hypoperfusion. Chronic microvas-cular injury is characterized by reactive prolifera-tion of vascular endothelial cells, thickening of theintima, fibrosis of the media, and narrowing of thelumens. Mural scarring reduces vascular complianceand compromises blood flow and nutrient delivery,particularly in periods of high metabolic demand.Moreover, blood vessel walls are rendered leaky andtherefore permeable to toxins due to their structuralweakness [105,106]. These effects could account forthe perivascular tissue attrition (widened perivascu-lar spaces) seen in brains of people with T2DM. InAD, restricted blood flow and oxygen/nutrient deliv-ery compounds the adverse effects of insulin/IGFresistance by further increasing oxidative stress,thereby activating signal transduction pathwaysthat promote aberrant tau phosphorylation, A�PP

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