Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease.

Interest in characterizing the role of impaired insulin actions in Alzheimer's disease (AD) and vascular dementia is growing exponentially. This review details what is currently known about insulin, insulin-like growth factor type I (IGF-I) and IGF-II proteins and their corresponding receptors in the brain, and delineates the major controversies pertaining to alterations in the expression and function of these molecules in AD. The various experimental animal models generated by over-expression, mutation, or depletion of genes that are critical to the insulin or IGF signaling cascades are summarized, noting the degrees to which they reproduce the histopathological, biochemical, molecular, or behavioral abnormalities associated with AD. Although no single model was determined to be truly representative of AD, depletion of the neuronal insulin receptor and intracerebroventricular injection of Streptozotocin reproduce a number of important aspects of AD-type neurodegeneration, and therefore provide supportive evidence that AD may be caused in part by neuronal insulin resistance, i.e. brain diabetes. The extant literature did not resolve whether the CNS insulin resistance in AD represents a local disease process, or complication/extension of peripheral insulin resistance, i.e. chronic hyperglycemia, hyperinsulinemia, and Type 2 diabetes mellitus. The available epidemiological data are largely inconclusive with regard to the contribution of Type 2 diabetes mellitus to cognitive impairment and AD-type neurodegeneration. A major conclusion drawn from this review is that there is a genuine need for thorough and comprehensive study of the neuropathological changes associated with diabetes mellitus, in the presence or absence of superimposed AD or vascular dementia. Strategies for intervention may depend entirely upon whether the CNS disease processes are mediated by peripheral, central, or both types of insulin resistance.

[1]  S. Doré,et al.  Insulin-like growth factor-1 (IGF-1): a neuroprotective trophic factor acting via the Akt kinase pathway. , 2000, Journal of neural transmission. Supplementum.

[2]  P. H. Seeburg,et al.  Human insulin receptor and its relationship to the tyrosine kinase family of oncogenes , 1985, Nature.

[3]  M. Viitanen,et al.  Insulin-like growth factors and insulin-like growth factor binding proteins in cerebrospinal fluid and serum of patients with dementia of the Alzheimer type , 1993, Journal of neural transmission. Parkinson's disease and dementia section.

[4]  B. Burgering,et al.  Essential Role for Protein Kinase B (PKB) in Insulin-induced Glycogen Synthase Kinase 3 Inactivation , 1998, The Journal of Biological Chemistry.

[5]  J. Woodgett,et al.  Phosphoinositide-3-OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[6]  D. Puro,et al.  Insulin-mediated regulation of neuronal maturation. , 1984, Science.

[7]  J. Newcomer,et al.  Enhancement of memory in Alzheimer disease with insulin and somatostatin, but not glucose. , 1999, Archives of general psychiatry.

[8]  G. Glenner,et al.  Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. , 1984, Biochemical and biophysical research communications.

[9]  B. Doble,et al.  GSK-3: tricks of the trade for a multi-tasking kinase , 2003, Journal of Cell Science.

[10]  K. Heidenreich,et al.  Insulin receptors mediate growth effects in cultured fetal neurons. I. Rapid stimulation of protein synthesis. , 1989, Endocrinology.

[11]  R. Maccioni,et al.  Iron-induced oxidative stress modify tau phosphorylation patterns in hippocampal cell cultures , 2003, Biometals.

[12]  G. Zuliani,et al.  Alzheimer Disease and Vascular Dementia: Relationships with Fasting Glucose and Insulin Levels , 2000, Dementia and Geriatric Cognitive Disorders.

[13]  D. Selkoe,et al.  Neurons Regulate Extracellular Levels of Amyloid β-Protein via Proteolysis by Insulin-Degrading Enzyme , 2000, The Journal of Neuroscience.

[14]  H. Braak,et al.  Role of protein kinase B in Alzheimer's neurofibrillary pathology , 2003, Acta Neuropathologica.

[15]  C. Kahn,et al.  Printed in U.S.A. Copyright © 1999 by The Endocrine Society Postnatal Growth Responses to Insulin-Like Growth Factor I in Insulin Receptor Substrate-1-Deficient Mice* , 2022 .

[16]  P. Ye,et al.  In vivo actions of insulin-like growth factor-I (IGF-I) on cerebellum development in transgenic mice: evidence that IGF-I increases proliferation of granule cell progenitors. , 1996, Brain research. Developmental brain research.

[17]  Ling Xie,et al.  Alzheimer's β-Amyloid Peptides Compete for Insulin Binding to the Insulin Receptor , 2002, The Journal of Neuroscience.

[18]  K. Hirayama,et al.  Loss of insulin receptor immunoreactivity from the substantia nigra pars compacta neurons in Parkinson's disease , 1994, Acta Neuropathologica.

[19]  F. Crews,et al.  Binding of [125I]-insulin-like growth factor-1 (IGF-1) in brains of Alzheimer's and alcoholic patients. , 1991, Advances in experimental medicine and biology.

[20]  R. Kulkarni,et al.  Tissue-specific targeting of the insulin receptor gene , 2002, Endocrine.

[21]  A. Hofman,et al.  Non-insulin-dependent Diabetes Mellitus (niddm) Association of Diabetes Mellitus and Dementia: the Rotterdam Study , 2022 .

[22]  C. Kahn,et al.  Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance , 2002, Clinical endocrinology.

[23]  M. Billingsley,et al.  Tau phosphorylation in brain slices: pharmacological evidence for convergent effects of protein phosphatases on tau and mitogen-activated protein kinase. , 1995, Molecular pharmacology.

[24]  S. Hoyer,et al.  Oxidative metabolism deficiencies in brains of patients with Alzheimer's disease , 1996, Acta neurologica Scandinavica. Supplementum.

[25]  S. Hoyer.  Age as Risk Factor for Sporadic Dementia of the Alzheimer Type? , 1994, Annals of the New York Academy of Sciences.

[26]  M. Carson,et al.  Insulin-like growth factor I increases brain growth and central nervous system myelination in tTransgenic mice , 1993, Neuron.

[27]  P. Ye,et al.  The role of the insulin-like growth factors in the central nervous system , 1996, Molecular Neurobiology.

[28]  Y. Kido,et al.  Distinct and overlapping functions of insulin and IGF-I receptors. , 2001, Endocrine reviews.

[29]  D. Selkoe,et al.  Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[30]  V. Lee,et al.  Insulin and Insulin-like Growth Factor-1 Regulate Tau Phosphorylation in Cultured Human Neurons* , 1997, The Journal of Biological Chemistry.

[31]  Y. Sheline,et al.  Memory improvement following induced hyperinsulinemia in alzheimer's disease , 1996, Neurobiology of Aging.

[32]  Simon Lovestone,et al.  Alzheimer's disease-like phosphorylation of the microtubule-associated protein tau by glycogen synthase kinase-3 in transfected mammalian cells , 1994, Current Biology.

[33]  D. Selkoe,et al.  Enhanced Proteolysis of β-Amyloid in APP Transgenic Mice Prevents Plaque Formation, Secondary Pathology, and Premature Death , 2003, Neuron.

[34]  S. Hoyer.  Brain glucose and energy metabolism abnormalities in sporadic Alzheimer disease. Causes and consequences: an update , 2000, Experimental Gerontology.

[35]  M. Chao,et al.  Insulin, insulin-like growth factor II, and nerve growth factor effects on tubulin mRNA levels and neurite formation. , 1985, Proceedings of the National Academy of Sciences of the United States of America.

[36]  C. Messier.  Diabetes, Alzheimer's disease and apolipoprotein genotype , 2003, Experimental Gerontology.

[37]  L. Frölich,et al.  Altered regulation of brain glucose metabolism as a cause of neurodegenerative disorders? , 1995, Journal of neural transmission. Supplementum.

[38]  S. Doré,et al.  Protective and Rescuing Abilities of IGF‐I and Some Putative Free Radical Scavengers against β‐Amyloid‐Inducing Toxicity in Neurons , 1999, Annals of the New York Academy of Sciences.

[39]  George Perry,et al.  The Role of Mitogen-Activated Protein Kinase Pathways in Alzheimer’s Disease , 2002, Neurosignals.

[40]  R. Rozmahel,et al.  Presenilin mutations associated with Alzheimer disease cause defective intracellular trafficking of β-catenin,a component of the presenilin protein complex , 1999, Nature Medicine.

[41]  N. Hay,et al.  Akt, a Target of Phosphatidylinositol 3-Kinase, Inhibits Apoptosis in a Differentiating Neuronal Cell Line , 1998, Molecular and Cellular Biology.

[42]  M. White,et al.  The IRS-1 signaling system. , 1994, Trends in biochemical sciences.

[43]  P. Ye,et al.  Deficient expression of insulin receptor substrate-1 (IRS-1) fails to block insulin-like growth factor-I (IGF-I) stimulation of brain growth and myelination. , 2002, Brain research. Developmental brain research.

[44]  R. Nitsch,et al.  Predominant abnormality in cerebral glucose utilization in late-onset dementia of the Alzheimer type: A cross-sectional comparison against advanced late-onset and incipient early-onset cases , 1991, Journal of neural transmission. Parkinson's disease and dementia section.

[45]  D. Kimelman,et al.  Role of Glycogen Synthase Kinase-3β in Neuronal Apoptosis Induced by Trophic Withdrawal , 2000, The Journal of Neuroscience.

[46]  Y. Miyazaki,et al.  Rosiglitazone improves downstream insulin receptor signaling in type 2 diabetic patients. , 2003, Diabetes.

[47]  S. Srinivasula,et al.  Caspase Cleavage Enhances the Apoptosis-Inducing Effects of BAD , 2001, Molecular and Cellular Biology.

[48]  David R. Kaplan,et al.  Regulation of Neuronal Survival by the Serine-Threonine Protein Kinase Akt , 1997, Science.

[49]  B. Winblad,et al.  Decreased Plasma Insulin-Like Growth Factor-I Level in Familial Alzheimer’s Disease Patients Carrying the Swedish APP 670/671 Mutation , 1999, Dementia and Geriatric Cognitive Disorders.

[50]  G. Meneilly,et al.  Alterations in Glucose Metabolism in Patients with Alzheimer's Disease , 1993, Journal of the American Geriatrics Society.

[51]  P. Ye,et al.  Regulation of insulin-like growth factor I (IGF-I) gene expression in brain of transgenic mice expressing an IGF-I-luciferase fusion gene. , 1997, Endocrinology.

[52]  J. Heitner,et al.  Diabetics do not have increased Alzheimer-type pathology compared with age-matched control subjects , 1997, Neurology.

[53]  S. Hoyer,et al.  Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus , 1993, International Journal of Developmental Neuroscience.

[54]  G. Evin,et al.  Biogenesis and metabolism of Alzheimer’s disease Aβ amyloid peptides , 2002, Peptides.

[55]  K. M. Shaffer,et al.  Characterization of H2O2‐induced acute apoptosis in cultured neural stem/progenitor cells , 2004, FEBS letters.

[56]  S. Hoyer,et al.  The aging brain. Changes in the neuronal insulin/insulin receptor signal transduction cascade trigger late-onset sporadic Alzheimer disease (SAD). A mini-review , 2002, Journal of Neural Transmission.

[57]  J. Reubi,et al.  Somatostatin and Alzheimer's disease: a hypothesis , 1986, Journal of Neurology.

[58]  E. Roberts,et al.  Energy Substrates for Neurons during Neural Activity: A Critical Review of the Astrocyte-Neuron Lactate Shuttle Hypothesis , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[59]  A. Saltiel,et al.  Insulin signaling pathways in time and space. , 2002, Trends in cell biology.

[60]  Angus M. Brown,et al.  Energy transfer from astrocytes to axons: the role of CNS glycogen , 2004, Neurochemistry International.

[61]  B. Burgering,et al.  Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction , 1995, Nature.

[62]  S. Hoyer,et al.  Is sporadic Alzheimer disease the brain type of non-insulin dependent diabetes mellitus? A challenging hypothesis , 1998, Journal of Neural Transmission.

[63]  L. Velloso,et al.  Effects of age on elements of insulin-signaling pathway in central nervous system of rats , 2001, Endocrine.

[64]  J. Blass,et al.  The role of the metabolic lesion in Alzheimer's disease. , 2002, Journal of Alzheimer's disease : JAD.

[65]  H. Lithell,et al.  Peripheral glucose metabolism and insulin sensitivity in Alzheimer's disease , 1993, Acta neurologica Scandinavica.

[66]  G. G. Stokes.  "J." , 1890, The New Yale Book of Quotations.

[67]  G. Sesti,et al.  Insulin receptor substrate (IRS) transduction system: distinct and overlapping signaling potential , 2000, Diabetes/metabolism research and reviews.

[68]  J. Kushner,et al.  Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation , 2003, The Journal of Neuroscience.

[69]  P. J. Koudstaal,et al.  Type 2 diabetes and atrophy of medial temporal lobe structures on brain MRI , 2003, Diabetologia.

[70]  A. Klippel,et al.  Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase, and Akt , 1997, Molecular and cellular biology.

[71]  S. Hoyer,et al.  The brain insulin signal transduction system and sporadic (type II) Alzheimer disease: an update , 2002, Journal of Neural Transmission.

[72]  P. S. St George-Hyslop,et al.  Presenilin function: connections to Alzheimer's disease and signal transduction. , 2001, Biochemical Society symposium.

[73]  D. Campion,et al.  Polymorphisms of insulin degrading enzyme gene are not associated with Alzheimer's disease , 2002, Neuroscience Letters.

[74]  I. Nishimoto,et al.  Characterization of the toxic mechanism triggered by Alzheimer's amyloid‐β peptides via p75 neurotrophin receptor in neuronal hybrid cells , 2003, Journal of neuroscience research.

[75]  Andrew J. Crossthwaite,et al.  Hydrogen peroxide‐mediated phosphorylation of ERK1/2, 
Akt/PKB and JNK in cortical neurones: dependence 
on Ca2+ and PI3‐kinase , 2002, Journal of neurochemistry.

[76]  J. Livingston,et al.  Insulin receptors in the central nervous system: Localization, signalling mechanisms and functional aspects , 1991, Progress in Neurobiology.

[77]  N. Wilczak,et al.  Insulin-like growth factor-I receptor densities in human frontal cortex and white matter during aging, in Alzheimer's disease, and in Huntington's disease , 1994, Neuroscience Letters.

[78]  B. Ghetti,et al.  Inhibition of insulin‐like growth factor I activity contributes to the premature apoptosis of cerebellar granule neuron in weaver mutant mice: In vitro analysis , 2002, Journal of neuroscience research.

[79]  H. Brody,et al.  The aging brain , 1992, Acta neurologica Scandinavica. Supplementum.

[80]  J. O’Kusky,et al.  Increased insulin-like growth factor-I (IGF-I) expression during early postnatal development differentially increases neuron number and growth in medullary nuclei of the mouse. , 1999, Brain research. Developmental brain research.

[81]  G. Schellenberg,et al.  Cerebrospinal fluid and plasma insulin levels in Alzheimer's disease , 1998, Neurology.

[82]  E. Helmes,et al.  Metabolic Changes in Alzheimer's Disease , 1988, Journal of the American Geriatrics Society.

[83]  G. Zuliani,et al.  Alzheimer disease and vascular dementia: relationships with fasting glucose and insulin levels. , 1999, Dementia and geriatric cognitive disorders.

[84]  J. Cresto,et al.  Degradation of Soluble Amyloid β-Peptides 1–40, 1–42, and the Dutch Variant 1–40Q by Insulin Degrading Enzyme from Alzheimer Disease and Control Brains , 2000, Neurochemical Research.

[85]  J. O’Kusky,et al.  In vivo effects of insulin‐like growth factor‐I (IGF‐I) on prenatal and early postnatal development of the central nervous system , 2004, The European journal of neuroscience.

[86]  A Hofman,et al.  Diabetes mellitus and the risk of dementia , 1999, Neurology.

[87]  J. Wands,et al.  Alzheimer-associated neuronal thread protein mediated cell death is linked to impaired insulin signaling. , 2004, Journal of Alzheimer's disease : JAD.

[88]  D. Selkoe,et al.  Partial loss-of-function mutations in insulin-degrading enzyme that induce diabetes also impair degradation of amyloid beta-protein. , 2004, The American journal of pathology.

[89]  L. Frölich,et al.  A Disturbance in the Neuronal Insulin Receptor Signal Transduction in Sporadic Alzheimer's Disease , 1999, Annals of the New York Academy of Sciences.

[90]  R. Quirion,et al.  Insulin‐like growth factor‐I and its receptor in the frontal cortex, hippocampus, and cerebellum of normal human and Alzheimer disease brains , 2000, Synapse.

[91]  J. Unger,et al.  Immunohistochemical localization of insulin receptors and phosphotyrosine in the brainstem of the adult rat , 1991, Neuroscience.

[92]  J. Newcomer,et al.  Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type: a longitudinal study. , 1993, Behavioral neuroscience.

[93]  R. Duara,et al.  Confirmation of association between D10S583 and Alzheimer's disease in a case–control sample , 2002, Neuroscience Letters.

[94]  A. D'ercole.  Expression of Insulin‐like Growth Factor‐I in Transgenic Mice a , 1993, Annals of the New York Academy of Sciences.

[95]  Miss A.O. Penney.  (b) , 1974, The New Yale Book of Quotations.

[96]  S. Hoyer,et al.  Inhibition of the Neuronal Insulin Receptor Causes Alzheimer‐like Disturbances in Oxidative/Energy Brain Metabolism and in Behavior in Adult Rats , 1999, Annals of the New York Academy of Sciences.

[97]  M. White,et al.  Pleiotropic insulin signals are engaged by multisite phosphorylation of IRS-1 , 1993, Molecular and cellular biology.

[98]  J. Wands,et al.  Chronic gestational exposure to ethanol impairs insulin-stimulated survival and mitochondrial function in cerebellar neurons , 2002, Cellular and Molecular Life Sciences CMLS.

[99]  S. Hoyer.  Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic implications. , 2004, Advances in experimental medicine and biology.

[100]  S. Hoyer,et al.  Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. , 1998, Behavioral neuroscience.

[101]  E. Yavin,et al.  Pro‐apoptotic signaling in neuronal cells following iron and amyloid beta peptide neurotoxicity , 2003, Journal of neurochemistry.

[102]  S. M. de la Monte,et al.  Transient hypoxia causes Alzheimer-type molecular and biochemical abnormalities in cortical neurons: potential strategies for neuroprotection. , 2003, Journal of Alzheimer's disease : JAD.

[103]  M G McInnis,et al.  Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. , 2000, Science.

[104]  M. Gagnon,et al.  Glucose regulation and cognitive functions: relation to Alzheimer's disease and diabetes , 1996, Behavioural Brain Research.

[105]  B. Winblad,et al.  Accumulation of cyclin-dependent kinase 5 (cdk5) in neurons with early stages of Alzheimer's disease neurofibrillary degeneration , 1998, Brain Research.

[106]  G. Dienel,et al.  Glucose and lactate metabolism during brain activation , 2001, Journal of neuroscience research.

[107]  P. Greengard,et al.  Does insulin dysfunction play a role in Alzheimer's disease? , 2002, Trends in pharmacological sciences.

[108]  K. Heidenreich,et al.  Insulin receptors mediate growth effects in cultured fetal neurons. II. Activation of a protein kinase that phosphorylates ribosomal protein S6. , 1989, Endocrinology.

[109]  B. Bogerts,et al.  Insulin-degrading enzyme in the Alzheimer's disease brain: prominent localization in neurons and senile plaques , 1999, Neuroscience Letters.

[110]  L. Hersh,et al.  Insulin-degrading Enzyme Regulates Extracellular Levels of Amyloid β-Protein by Degradation* , 1998, The Journal of Biological Chemistry.

[111]  S. R. Datta,et al.  Akt Phosphorylation of BAD Couples Survival Signals to the Cell-Intrinsic Death Machinery , 1997, Cell.

[112]  C. Kahn,et al.  Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus: what can we learn from transgenic and knockout mice? , 2000, Diabetes & metabolism.

[113]  E. Mandelkow,et al.  Clogging of axons by tau, inhibition of axonal traffic and starvation of synapses , 2003, Neurobiology of Aging.

[114]  M. Owen,et al.  Substantial linkage disequilibrium across the insulin-degrading enzyme locus but no association with late-onset Alzheimer's disease , 2001, Human Genetics.

[115]  S. Doré,et al.  Insulin-like growth factor I protects and rescues hippocampal neurons against beta-amyloid- and human amylin-induced toxicity. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[116]  N. Ruderman,et al.  The phosphatidylinositol 3-kinase serine kinase phosphorylates IRS-1. Stimulation by insulin and inhibition by Wortmannin. , 1994, The Journal of biological chemistry.

[117]  S. Hoyer.  Neurodegeneration, Alzheimer's disease, and beta-amyloid toxicity. , 1994, Life sciences.

[118]  K. Duff,et al.  Permeability of Proteins at the Blood–Brain Barrier in the Normal Adult Mouse and Double Transgenic Mouse Model of Alzheimer's Disease , 2001, Neurobiology of Disease.

[119]  G. Cooper,et al.  Role of Glycogen Synthase Kinase-3 in the Phosphatidylinositol 3-Kinase/Akt Cell Survival Pathway* , 1998, The Journal of Biological Chemistry.

[120]  Min-Seon Kim,et al.  Peroxisome Proliferator-Activated Receptor (PPAR)-α Activation Prevents Diabetes in OLETF Rats: Comparison With PPAR-γ Activation , 2003 .

[121]  Effects of hyperglycemia on memory and hormone levels in dementia of the Alzheimer type: a longitudinal study. , 1993 .

[122]  D. Alessi,et al.  The role of PI 3-kinase in insulin action. , 1998, Biochimica et biophysica acta.

[123]  Johanna Kuusisto,et al.  Association between features of the insulin resistance syndrome and alzheimer's disease independently of apolipoprotein e4 phenotype: cross sectional population based study , 1997, BMJ.

[124]  J. Nagy,et al.  Impaired brain development and reduced astrocyte response to injury in transgenic mice expressing IGF binding protein-1 , 1997, Brain Research.

[125]  Matthew P. Frosch,et al.  Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[126]  Jesús Avila,et al.  Glycogen synthase kinase 3: a drug target for CNS therapies , 2004, Journal of neurochemistry.

[127]  J. O’Kusky,et al.  Insulin-Like Growth Factor-I Promotes Neurogenesis and Synaptogenesis in the Hippocampal Dentate Gyrus during Postnatal Development , 2000, The Journal of Neuroscience.

[128]  J. Wands,et al.  Ethanol impairs insulin-stimulated mitochondrial function in cerebellar granule neurons , 2001, Cellular and Molecular Life Sciences CMLS.

[129]  F. Jiménez-Jiménez,et al.  Cerebrospinal fluid levels of insulin in patients with Alzheimer's disease , 2002, Acta neurologica Scandinavica.

[130]  I. Cantuti-Castelvetri,et al.  The spin trapping agent PBN stimulates H2O2-induced Erk and Src kinase activity in human neuroblastoma cells , 2002, Neuroreport.

[131]  E. Doran,et al.  Mitochondria and cell death. , 2000, Biochemical Society transactions.

[132]  P. Vollenweider.  Insulin Resistant States and Insulin Signaling , 2003, Clinical chemistry and laboratory medicine.

[133]  P. Gluckman,et al.  Insulin-like growth factor-I (IGF-I) immunoreactivity in the Alzheimer's disease temporal cortex and hippocampus. , 1997, Brain research. Molecular brain research.

[134]  G. Kroemer,et al.  Mitochondrial permeability transition in apoptosis and necrosis , 2005, Cell Death and Differentiation.

[135]  C. Kahn,et al.  Role for neuronal insulin resistance in neurodegenerative diseases. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[136]  R. Martins,et al.  Amyloid beta antagonizes insulin promoted secretion of the amyloid beta protein precursor. , 2002, Journal of Alzheimer's disease : JAD.

[137]  E. Travis Littledike,et al.  Insulin , 1923, The Indian medical gazette.

[138]  S. Hoyer.  Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. , 2004, European journal of pharmacology.

[139]  Use of transgenic mice for understanding the physiology of insulin-like growth factors. , 1996, Hormone research.

[140]  Bengt Winblad,et al.  Akt activity in Alzheimer's disease and other neurodegenerative disorders , 2004, Neuroreport.

[141]  N. Brown,et al.  Partial rescue of ethanol-induced neuronal apoptosis by growth factor activation of phosphoinositol-3-kinase. , 2000, Alcoholism, clinical and experimental research.

[142]  A. S. Balasubramanian.  Amyloid Beta Peptide Processing, Insulin Degrading Enzyme, and Butyrylcholinesterase , 2001, Neurochemical Research.

[143]  M. Raizada,et al.  Insulin‐Like Growth Factor I Receptor Binding in Brains of Alzheimer's and Alcoholic Patients , 1992, Journal of neurochemistry.

[144]  Sanjay Asthana,et al.  Insulin Metabolism in Alzheimer’s Disease Differs According to Apolipoprotein E Genotype and Gender , 1999, Neuroendocrinology.

[145]  K. Akiyama,et al.  Increased insulin levels after OGTT load in peripheral blood and cerebrospinal fluid of patients with dementia of Alzheimer type , 1991, Biological Psychiatry.

[146]  B. Hyman,et al.  Cerebrovascular Pathology Contributes to the Heterogeneity of Alzheimer's Disease. , 1998, Journal of Alzheimer's disease : JAD.

[147]  Giancarlo V. De Ferrari and,et al.  Wnt signaling function in Alzheimer’s disease , 2000, Brain Research Reviews.

[148]  S. Hoyer,et al.  Inhibition of the Neuronal Insulin Receptor An in Vivo Model for Sporadic Alzheimer Disease? , 2000, Annals of the New York Academy of Sciences.

[149]  K. Gerozissis.  Brain Insulin: Regulation, Mechanisms of Action and Functions , 2003, Cellular and Molecular Neurobiology.

[150]  K. Jellinger,et al.  Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease , 1998, Journal of Neural Transmission.

[151]  E. Yavin,et al.  ERK activation and nuclear translocation in amyloid‐β peptide‐ and iron‐stressed neuronal cell cultures , 2002, The European journal of neuroscience.

[152]  C. Duyckaerts,et al.  Impaired brain development and hydrocephalus in a line of transgenic mice with liver-specific expression of human insulin-like growth factor binding protein-1. , 2000, Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society.

[153]  M. Memo,et al.  Alzheimer's disease linking neurodegeneration with neurodevelopment. , 2003, Functional neurology.

[154]  Min-Seon Kim,et al.  Peroxisome proliferator-activated receptor (PPAR)-alpha activation prevents diabetes in OLETF rats: comparison with PPAR-gamma activation. , 2003, Diabetes.

[155]  M. Raizada,et al.  The cellular and physiological actions of insulin in the central nervous system , 1993, Neurochemistry International.

[156]  B. Winblad,et al.  Changes in blood glucose and insulin secretion in patients with senile dementia of Alzheimer type. , 2009, Acta medica Scandinavica.

[157]  C. Kahn,et al.  The early intracellular signaling pathway for the insulin/insulin-like growth factor receptor family in the mammalian central nervous system , 1996, Molecular Neurobiology.

[158]  Shirley Dex,et al.  JR 旅客販売総合システム（マルス）における運用及び管理について , 1991 .

[159]  L. Wetterberg,et al.  Insulin‐like growth factors and somatomedin B in the cerebrospinal fluid of patients with dementia of the Alzheimer type , 1988, Acta psychiatrica Scandinavica.

[160]  J. Mcdermott,et al.  Degradation of Alzheimer's ß-Amyloid Protein by Human and Rat Brain Peptidases: Involvement of Insulin-Degrading Enzyme , 2004, Neurochemical Research.

[161]  G. Wilcock,et al.  Hyperinsulinaemia and Alzheimer's disease. , 1994, Age and ageing.

[162]  S. Hoyer,et al.  Desensitization of brain insulin receptor. Effect on glucose/energy and related metabolism. , 1994, Journal of neural transmission. Supplementum.

[163]  L. Tsai,et al.  Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration , 1999, Nature.

[164]  J. O’Kusky,et al.  Mutant mouse models of insulin-like growth factor actions in the central nervous system , 2002, Neuropeptides.

[165]  C. Kahn,et al.  Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. , 1999, The Journal of clinical investigation.

[166]  J. C. Torre,et al.  Critically attained threshold of cerebral hypoperfusion: the CATCH hypothesis of Alzheimer’s pathogenesis , 2000, Neurobiology of Aging.

[167]  J. Nichols,et al.  Nutritional status of patients with Alzheimer's disease: a 1-year study. , 1996, Journal of the American Dietetic Association.

[168]  G. Schellenberg,et al.  Reduced Hippocampal Insulin-Degrading Enzyme in Late-Onset Alzheimer's Disease Is Associated with the Apolipoprotein E-ε4 Allele , 2003 .

[169]  M. Carson,et al.  Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. , 1993, Neuron.

[170]  R. Nitsch,et al.  Cerebral excess release of neurotransmitter amino acids subsequent to reduced cerebral glucose metabolism in early-onset dementia of Alzheimer type , 2005, Journal of Neural Transmission.

[171]  S. Hoyer,et al.  Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats , 1994, International Journal of Developmental Neuroscience.

[172]  R. Martins,et al.  Insulin Effects on Glucose Metabolism, Memory, and Plasma Amyloid Precursor Protein in Alzheimer's Disease Differ According to Apolipoprotein‐E Genotype , 2000, Annals of the New York Academy of Sciences.

[173]  Sanjay Asthana,et al.  Insulin dose–response effects on memory and plasma amyloid precursor protein in Alzheimer’s disease: interactions with apolipoprotein E genotype , 2003, Psychoneuroendocrinology.

[174]  M. Pertseva,et al.  Structural and functional characterization of insulin receptor substrate proteins and the molecular mechanisms of their interaction with insulin superfamily tyrosine kinase receptors and effector proteins. , 2000, Membrane & cell biology.

[175]  P. Greengard,et al.  Stimulation of β-Amyloid Precursor Protein Trafficking by Insulin Reduces Intraneuronal β-Amyloid and Requires Mitogen-Activated Protein Kinase Signaling , 2001, The Journal of Neuroscience.