New roles for insulin-like hormones in neuronal signalling and protection: New hopes for novel treatments of Alzheimer’s disease?

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD). This is most likely due to the desensitisation of insulin receptors in the brain. Insulin acts as a growth factor and supports neuronal repair, dendritic sprouting, and differentiation. This review discusses the potential role that insulin-like hormones could play in ameliorating the reduced growth factor signalling in the brains of people with AD. The incretins glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have very similar properties in protecting neurons from toxic effects, and are capable of reversing the detrimental effects that beta-amyloid fragments have on synaptic plasticity. Therefore, incretins show great promise as a novel treatment for reducing degenerative processes in AD.

[1]  G. Ning,et al.  GLP-1 amplifies insulin signaling by up-regulation of IRβ, IRS-1 and Glut4 in 3T3-L1 adipocytes , 2007, Endocrine.

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

[3]  N. Greig,et al.  Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer's disease. , 2005, Current Alzheimer research.

[4]  B. Göke,et al.  Five Out of Six Tryptophan Residues in the N-Terminal Extracellular Domain of the Rat GLP-1 Receptor Are Essential for its Ability to Bind GLP-1 , 1997, Peptides.

[5]  T. Kameyama,et al.  Glucagon-like peptide-1 modulates neuronal activity in the rat's hippocampus. , 1999, Neuroreport.

[6]  S. Hoyer.  Models of Alzheimer's disease: cellular and molecular aspects. , 1997, Journal of neural transmission. Supplementum.

[7]  S. Seino,et al.  Localization of the ATP-Sensitive K+ Channel Subunit Kir6.2 in Mouse Pancreas , 1997, Diabetes.

[8]  J. Habener,et al.  Expression of cAMP-regulated guanine nucleotide exchange factors in pancreatic beta-cells. , 2000, Biochemical and biophysical research communications.

[9]  J. Holst.  The physiology of glucagon-like peptide 1. , 2007, Physiological reviews.

[10]  W. K. Cullen,et al.  β‐Amyloid produces a delayed NMDA receptor‐ dependent reduction in synaptic transmission in rat hippocampus , 1996, Neuroreport.

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

[12]  D. Selkoe,et al.  Natural oligomers of the amyloid-β protein specifically disrupt cognitive function , 2005, Nature Neuroscience.

[13]  Lin Li.  Is Glucagon-like peptide-1, an agent treating diabetes, a new hope for Alzheimer’s disease? , 2007, Neuroscience Bulletin.

[14]  C. Bailey,et al.  A Novel, Long-Acting Agonist of Glucose-Dependent Insulinotropic Polypeptide Suitable for Once-Daily Administration in Type 2 Diabetes , 2005, Journal of Pharmacology and Experimental Therapeutics.

[15]  C. Hölscher,et al.  Impairments of hippocampal synaptic plasticity induced by aggregated beta-amyloid (25–35) are dependent on stimulation-protocol and genetic background , 2007, Experimental Brain Research.

[16]  B. Gallwitz,et al.  Therapies for the treatment of type 2 diabetes mellitus based on incretin action. , 2006, Minerva endocrinologica.

[17]  S. Nakanishi,et al.  Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibitory cyclic AMP signal transduction. , 1994, The Journal of biological chemistry.

[18]  N. Greig,et al.  Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy , 2007, Experimental Neurology.

[19]  G. Biessels,et al.  Glucose, insulin and the brain: modulation of cognition and synaptic plasticity in health and disease: a preface. , 2004, European journal of pharmacology.

[20]  E. Krebs,et al.  Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. , 1999, Diabetes.

[21]  E. Krebs,et al.  Leptin Induces Insulin-like Signaling That Antagonizes cAMP Elevation by Glucagon in Hepatocytes* , 2000, The Journal of Biological Chemistry.

[22]  C. Finch,et al.  Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[23]  C. Hölscher,et al.  Protease-resistant glucose-dependent insulinotropic polypeptide agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. , 2008, Journal of neurophysiology.

[24]  J. Wands,et al.  Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[25]  C. Ackerley,et al.  Recruitment of functional GABAA receptors to postsynaptic domains by insulin , 1997, Nature.

[26]  M. Ristow,et al.  Neurodegenerative disorders associated with diabetes mellitus , 2004, Journal of Molecular Medicine.

[27]  C. Hölscher,et al.  GLP-1 agonists facilitate hippocampal LTP and reverse the impairment of LTP induced by beta-amyloid. , 2008, European journal of pharmacology.

[28]  N. Irwin,et al.  Effects of short-term chemical ablation of the GIP receptor on insulin secretion, islet morphology and glucose homeostasis in mice , 2004, Biological chemistry.

[29]  J. Oka,et al.  Endogenous GLP-1 is involved in β-amyloid protein-induced memory impairment and hippocampal neuronal death in rats , 2000, Brain Research.

[30]  S. Bloom,et al.  Nonpeptidic glucagon-like peptide 1 receptor agonists: A magic bullet for diabetes? , 2007, Proceedings of the National Academy of Sciences.

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

[32]  A. Kastin,et al.  Entry of exendin-4 into brain is rapid but may be limited at high doses , 2003, International Journal of Obesity.

[33]  C. Herron,et al.  Blockade of long-term potentiation by beta-amyloid peptides in the CA1 region of the rat hippocampus in vivo. , 2001, Journal of neurophysiology.

[34]  P. Flatt,et al.  Glucose-dependent insulinotropic polypeptide (GIP): anti-diabetic and anti-obesity potential? , 2003, Neuropeptides.

[35]  J. Harvey.  Leptin: a diverse regulator of neuronal function , 2007, Journal of neurochemistry.

[36]  W. Klein,et al.  Amyloid beta oligomers induce impairment of neuronal insulin receptors , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  S. Bonner-Weir,et al.  Insulinotropic glucagon-like peptide 1 agonists stimulate expression of homeodomain protein IDX-1 and increase islet size in mouse pancreas. , 2000, Diabetes.

[38]  M. Haan.  Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer's disease , 2006, Nature Clinical Practice Neurology.

[39]  P. Ye,et al.  Insulin‐like growth factor actions during development of neural stem cells and progenitors in the central nervous system , 2006, Journal of neuroscience research.

[40]  M. Prentki,et al.  Glucagon-like peptide-1 promotes DNA synthesis, activates phosphatidylinositol 3-kinase and increases transcription factor pancreatic and duodenal homeobox gene 1 (PDX-1) DNA binding activity in beta (INS-1)-cells , 1999, Diabetologia.

[41]  A. Sima,et al.  Alzheimer-Like Changes in Rat Models of Spontaneous Diabetes , 2007, Diabetes.

[42]  C. Bailey,et al.  Metabolic Stability, Receptor Binding, cAMP Generation, Insulin Secretion and Antihyperglycaemic Activity of Novel N-Terminal Glu9-Substituted Analogues of Glucagon-Like Peptide-1 , 2003, Biological chemistry.

[43]  J. Wands,et al.  Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease--is this type 3 diabetes? , 2005, Journal of Alzheimer's disease : JAD.

[44]  C. Hölscher.  Synaptic plasticity and learning and memory: LTP and beyond , 1999, Journal of neuroscience research.

[45]  J. Wands,et al.  Insulin and insulin-like growth factor resistance with neurodegeneration in an adult chronic ethanol exposure model. , 2007, Alcoholism, clinical and experimental research.

[46]  J. Bockaert,et al.  Activation of a Large‐conductance Ca2+‐Dependent K+ Channel by Stimulation of Glutamate Phosphoinositide‐coupled Receptors in Cultured Cerebellar Granule Cells , 1991, The European journal of neuroscience.

[47]  G. Massicotte,et al.  Hippocampal synaptic plasticity and glutamate receptor regulation: influences of diabetes mellitus. , 2004, European journal of pharmacology.

[48]  P. Flatt,et al.  Comparative effects of GLP-1 and GIP on cAMP production, insulin secretion, and in vivo antidiabetic actions following substitution of Ala8/Ala2 with 2-aminobutyric acid. , 2004, Archives of biochemistry and biophysics.

[49]  M. Sheng,et al.  Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization , 2000, Nature Neuroscience.

[50]  W. Banks,et al.  Glucagon-like peptide-1 receptor is involved in learning and neuroprotection , 2003, Nature Medicine.

[51]  I. Torres-Aleman,et al.  Insulin-like growth factor I and Alzheimer´s disease: therapeutic prospects? , 2004, Expert review of neurotherapeutics.

[52]  M. Mattson,et al.  Glucagon‐like peptide 1 modulates calcium responses to glutamate and membrane depolarization in hippocampal neurons , 2003, Journal of neurochemistry.

[53]  P. Eriksson,et al.  Immunohistochemical distribution of glucose‐dependent insulinotropic polypeptide in the adult rat brain , 2007, Journal of neuroscience research.

[54]  Willem Hendrik Gispen,et al.  Cognition and synaptic plasticity in diabetes mellitus , 2000, Trends in Neurosciences.

[55]  F. Barkhof,et al.  Increased cortical atrophy in patients with Alzheimer’s disease and type 2 diabetes mellitus , 2005, Journal of Neurology, Neurosurgery & Psychiatry.

[56]  A. Irving,et al.  Leptin and its role in hippocampal synaptic plasticity. , 2006, Progress in lipid research.

[57]  J. Wands,et al.  Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer's disease. , 2006, Journal of Alzheimer's disease : JAD.

[58]  N. Greig,et al.  A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. , 2002, The Journal of pharmacology and experimental therapeutics.

[59]  C. Bailey,et al.  Novel Glucagon-Like Peptide-1 (GLP-1) Analog (Val8)GLP-1 Results in Significant Improvements of Glucose Tolerance and Pancreatic β-Cell Function after 3-Week Daily Administration in Obese Diabetic (ob/ob) Mice , 2006, Journal of Pharmacology and Experimental Therapeutics.

[60]  R. Mayeux,et al.  Hyperinsulinemia and risk of Alzheimer disease , 2004, Neurology.

[61]  Ronald C Petersen,et al.  Increased risk of type 2 diabetes in Alzheimer disease. , 2004, Diabetes.

[62]  P. Eriksson,et al.  Glucose-Dependent Insulinotropic Polypeptide Is Expressed in Adult Hippocampus and Induces Progenitor Cell Proliferation , 2005, The Journal of Neuroscience.

[63]  A M Graybiel,et al.  A family of cAMP-binding proteins that directly activate Rap1. , 1998, Science.

[64]  W. Pan,et al.  Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier , 2002, Journal of Molecular Neuroscience.

[65]  C. Bailey,et al.  Novel dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1(7-36)amide have preserved biological activities in vitro conferring improved glucose-lowering action in vivo. , 2003, Journal of molecular endocrinology.

[66]  I. Torres-Aleman,et al.  The role of insulin and insulin-like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer's disease. , 2004, European journal of pharmacology.

[67]  M. Mattson,et al.  beta-Amyloid peptides destabilize calcium homeostasis and render human cortical neurons vulnerable to excitotoxicity , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[68]  S. Bonner-Weir,et al.  Downregulation of GLP-1 and GIP Receptor Expression by Hyperglycemia , 2007, Diabetes.

[69]  J. Habener,et al.  Insulinotropic Glucagon-like Peptide-1-mediated Activation of Non-selective Cation Currents in Insulinoma Cells Is Mimicked by Maitotoxin* , 1997, The Journal of Biological Chemistry.

[70]  R. Zucker.  Calcium- and activity-dependent synaptic plasticity , 1999, Current Opinion in Neurobiology.

[71]  Hanspeter A Mallot,et al.  Soluble beta-amyloid[25-35] reversibly impairs hippocampal synaptic plasticity and spatial learning. , 2007, European journal of pharmacology.

[72]  F. Mora,et al.  Selective release of glutamine and glutamic acid produced by perfusion of GLP-1(7–36) amide in the basal ganglia of the conscious rat , 1992, Brain Research Bulletin.

[73]  K. Kaestner,et al.  Foxa2 Controls Pdx1 Gene Expression in Pancreatic β-Cells In Vivo , 2002 .

[74]  R. Tsien,et al.  Roles of N-type and Q-type Ca2+ channels in supporting hippocampal synaptic transmission. , 1994, Science.

[75]  P. Conn,et al.  Activation of metabotropic glutamate receptors increases cAMP accumulation in hippocampus by potentiating responses to endogenous adenosine , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[76]  J. Egan,et al.  Pharmacological Agents That Directly Modulate Insulin Secretion , 2003, Pharmacological Reviews.

[77]  N. Irwin,et al.  Stable agonist of glucose-dependent insulinotropic polypeptide (GIP) restores pancreatic beta cell glucose responsiveness but not glucose intolerance in aging mice , 2006, Experimental Gerontology.

[78]  N. Greig,et al.  Practical issues in stem cell therapy for Alzheimer's disease. , 2007, Current Alzheimer research.

[79]  N. Irwin,et al.  Effects of Subchronic Treatment With the Long-Acting Glucose-Dependent Insulinotropic Polypeptide Receptor Agonist, N-AcGIP, on Glucose Homeostasis in Streptozotocin-Induced Diabetes , 2007, Pancreas.

[80]  Christian Hölscher,et al.  Common pathological processes in Alzheimer disease and type 2 diabetes: A review , 2007, Brain Research Reviews.

[81]  Werner A. Scherbaum,et al.  Insulin and the CNS: effects on food intake, memory, and endocrine parameters and the role of intranasal insulin administration in humans , 2004, Physiology & Behavior.

[82]  P. J. Larsen,et al.  Distribution of GLP‐1 Binding Sites in the Rat Brain: Evidence that Exendin‐4 is a Ligand of Brain GLP‐1 Binding Sites , 1995, The European journal of neuroscience.

[83]  J. Holst,et al.  Cellular regulation of islet hormone secretion by the incretin hormone glucagon-like peptide 1 , 1998, Pflügers Archiv.

[84]  M. Mattson,et al.  Glucagon‐like peptide‐1 decreases endogenous amyloid‐β peptide (Aβ) levels and protects hippocampal neurons from death induced by Aβ and iron , 2003 .

[85]  A. Aleman,et al.  Insulin-like growth factor-I, cognition and brain aging. , 2004, European journal of pharmacology.

[86]  D. Selkoe,et al.  Effects of secreted oligomers of amyloid β‐protein on hippocampal synaptic plasticity: a potent role for trimers , 2006, The Journal of physiology.

[87]  C. Herron,et al.  Inhibition of l-type voltage dependent calcium channels causes impairment of long-term potentiation in the hippocampal CA1 region in vivo , 2003, Brain Research.