AAD  Vol.6 No.1 , March 2017
Role of GSK3β and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease
Abstract: Intracerebroventricular administration (ICV) of streptozotocin (STZ) in rats has been associated to desensitization of the insulin receptor (IR) and biochemical changes similar to those occurring in Alzheimer’s disease (AD) or older brains, so it has been proposed as a suitable model for studying some of the pathological features of AD sporadic type (SAD). In this study, we investigated the role of glycogen synthase kinase 3β (GSK3β) and protein phosphatase 2A (PP2A) in the regulation of the phosphorylation of tau (p-tau). Results showed that ICV-STZ treated rats had deficits in short- (1.5-h) and long-term (24- and 48-h) memory after one month of ICV-STZ treatment and six months relative to control rats. The memory deficit was associated to increasing [F(3, 12) = 31.48, p < 0.0001] p-tau in the hippocampus but not in prefrontal cortex (PFC). Likewise, STZ reduced phosphorylation of GSK3β (p-GSK3β) and PP2A in hippocampus and PFC, indicating that GSK3β and PP2A contributed to regulation of p-tau. These data supporting the model with ICV-STZ in rat are adequate to study the progressive memory impairment associated to hyperphosphorylation of tau and the cascade of insulin receptor signaling; confirm that phosphatidyl-inositol-3 kinase-protein kinase B (PI3K-PKB/Akt-GSK3β) and PP2A are involved in the modulation of proteins responsible for the regulation of neurodegeneration in AD.
Cite this paper: Ponce-Lopez, T. , Hong, E. , Abascal-Díaz, M. and Meneses, A. (2017) Role of GSK3β and PP2A on Regulation of Tau Phosphorylation in Hippocampus and Memory Impairment in ICV-STZ Animal Model of Alzheimer’s Disease. Advances in Alzheimer's Disease, 6, 13-31. doi: 10.4236/aad.2017.61002.

[1]   Querfurth, H.W. and La Ferla, F.M. (2010) Alzheimer’s Disease. The New England Journal of Medicine, 362, 329-344.

[2]   Selkoe, D.J. (2001) Alzheimer’s Disease Results from the Cerebral Accumulation and Cytotoxicity of Amyloid Beta-Protein. Journal of Alzheimer’s Disease, 3, 75-80.

[3]   Goedert, M. and Spillantini, M.G. (2006) A Century of Alzheimer’s Disease. Science, 314, 777-781.

[4]   Blennow, K., de Leon, M.J. and Zetterberg, H. (2000) Alzheimer’s Disease. The Lancet, 368, 387-403.

[5]   Buée, L., Bassiére, T. and Buée-Scherrer, V. (2000) Tau Protein Isoforms, Phosphorylation and Role in Neurodegenerative Disorders. Brain Research Review, 33, 95-130.

[6]   Van Dam, D. and De Deyn, P.P. (2011) Animal Models in the Drug Discovery Pipeline for Alzheimer’s Disease. British Journal of Pharmacology,164, 1285-1300.

[7]   Planel, E., Tatebayashi, Y., Miyasaka, T., Liu, L., Wang, L., Herman, M., Yu, W.H., Luchsinger, J.A., Wadzinski, B., Duff, K.E. and Takashima, A. (2007) Insulin Dysfunction Induces in Vivo Tau Hyperphosphorylation through Distinct Mechanisms. Journal of Neuroscience, 27, 13635-13648.

[8]   Planel, E., Yasutake, K., Fujita, S.C. and Ishiguro, K. (2001) Inhibition of Protein Phosphatase 2A Overrides Tau Protein Kinase I/Glycogen Synthase Kinase 3beta and Cyclin-Dependant Kinase 5 Inhibition and Results in Tau Hyperphosphorylation in the Hippocampus of Starved Mouse. The Journal of Biological Chemistry, 276, 34298-34306.

[9]   Wang, J.Z., Grundke-Iqbal, I. and Iqbal, K. (2007) Kinases and Phosphatases and Tau Sites Involved in Alzheimer Neurofibrillary Degeneration. European Journal of Neuroscience, 25, 59-68.

[10]   Waring, S.C. and Rosenberg, R.N. (2008) Genome-Wide Association Studies in Alzheimer Disease. Archives of Neurology, 65, 329-334.

[11]   El Khoury, N.B., Gratuze, M., Papon, M.-A., Bretteville, A. and Planel, E. (2014) Insulin Dysfunction and Tau Pathology. Frontiers in Cellular Neuroscience, 8, 22.

[12]   Frolich, L., Blum-Degen, D., Riederer, P. and Hoyer, S. (1999) A Disturbance in the Neuronal Insulin Receptor Signal Transduction in Sporadic Alzheimer’s Disease. Annals of the New York Academy of Sciences, 893, 290-293.

[13]   Gasparini, L., Netzer, W.J., Greengard, P. and Xu, H. (2002) Does Insulin Dysfunction Play a Role in Alzheimer’s Disease? Trends in Pharmacological Sciences, 23, 288-293.

[14]   Craft, S. and Watson, G.S. (2004) Insulin and Neurodegenerative Disease, Shared and Specific Mechanisms. The Lancet Neurology, 3, 169-178.

[15]   De La Monte, S.M., Longato, L., Tong, M. and Wands, J.R. (2009) Insulin Resistance and Neurodegeneration, Roles of Obesity, Type 2 Diabetes Mellitus and Non-Alcoholic Steatohepatitis. Current Opinion in Investigational Drugs, 10, 1049-1060.

[16]   De La, M. (2012) Contributions of Brain Insulin Resistance and Deficiency in Amyloid-Related Neurodegeneration in Alzheimer’s Disease. Drugs, 72, 49-66.

[17]   Plaschke, K., Kopitz, J., Siegelin, M., Schliebs, R., Salkovic-Petrisic, M., Riederer, P. and Hoyer, S. (2010) Insulin-Resistant Brain State after Intracerebroventricular Streptozotocin Injection Exacerbates Alzheimer-Like Changes in Tg2576 AbetaPP-Overexpressing Mice. Journal of Alzheimer’s Disease, 19, 691-704.

[18]   Talbot, K., Wang, H.Y., Kazi, H., Han, L.Y., Bakshi, K.P., Stucky, A., Fuino, R.L., Kawaguchi, K.R., Samoyedny, A.J., Wilson, R.S., Arvanitakis, Z., Schneider, J.A., Wolf, B.A., Bennett, D.A., Trojanowski, J.Q. and Arnold, S.E. (2012) Demonstrated Brain Insulin Resistance in Alzheimer’s Disease Patients Is Associated with IGF-1 Resistance, IRS-1 Dysregulation, and Cognitive Decline. Journal of Clinical Investigation, 122, 1316-1338.

[19]   Neumann, K.F., Rojo, L., Navarrete, L.P., Farías, G. and Maccioni, R.P. (2008) Insulin Resistance and Alzheimer’s Disease, Molecular Links & Clinical Implications. Current Alzheimer Research, 5, 438-447.

[20]   Leibson, C.L., Rocca, W.A., Hanson, V.A., Cha, R., Kokmen, E., O’Brien, P.C. and Palumbo, P.J. (1997) Risk of Dementia among Persons with Diabetes Mellitus, a Population-Based Cohort Study. American Journal of Epidemiology, 145, 301-308.

[21]   Stolk, R.P., Breteler, M.M., Ott, A., Pols, H.A., Lamberts, S.W., Grobbee, D.E. and Hofman, A. (1997) Insulin and Cognitive Function in an Elderly Population. The Rotterdam Study. Diabetes Care, 20, 792-795.

[22]   Li, X., Song, D.S. and Leng, S.X. (2015) Link between Type 2 Diabetes and Alzheimer’s Disease, from Epidemiology to Mechanism and Treatment. Clinical Interventions in Aging, 10, 549-560.

[23]   Wallum, B.J., Taborsky, G.J., Porte, D., Figlewicz, D.P., Jacobson, L., Beard, J.C., Ward, W.K. and Dorsa, D. (1987) Cerebrospinal Fluid Insulin Levels Increase during Intravenous Insulin Infusions in Man. The Journal of Clinical Endocrinology & Metabolism, 64, 190-194.

[24]   Nitsch, R. and Hoyer, S. (1991) Local Action of the Diabetogenic Drug, Streptozotocin, on Glucose and Energy Metabolism in Rat Brain Cortex. Neuroscience Letters, 128, 199-202.

[25]   Hellweg, R., Nitsch, R., Hock, C., Jaksch, M. and Hoyer, S. (1992) Nerve Growth Factor and Choline Acetyltransferase Activity Levels in the Rat Brain Following Experimental Impairment of Cerebral Glucose and Energy Metabolism. Journal of Neuroscience Research, 31, 479-486.

[26]   Plaschke, K. and Hoyer, S. (1993) Action of the Diabetogenic Drug Streptozotocin on Glycolytic and Glycogenolytic Metabolism in Adult Rat Brain Cortex and Hippocampus. International Journal of Developmental Neuroscience, 11, 477-483.

[27]   Duelli, R., Schrock, H., Kuschinsky, W. and Hoyer, S. (1994) Intracerebroventricular Injection of Streptozotocin Induces Discrete Local Changes in Cerebral Glucose Utilization in Rats. International Journal of Developmental Neuroscience, 12, 737-743.

[28]   Sharma, M. and Gupta, Y.K. (2001) Intracerebroventricular Injection of Streptozotocin in Rats Produces Both Oxidative Stress in the Brain and Cognitive Impairment. Life Sciences, 68, 1021-1029.

[29]   Paxinos, G. and Watson, C. (2005) The Rat Brain Stereotaxic Coordinates. Academic Press, Sidney.

[30]   Pathan, A.R., Viswanad, B., Sonkusare, S.K. and Ramarao, P. (2006) Chronic Administration of Pioglitazone Attenuates Intracerebroventricular Streptozotocin Induced-Memory Impairment in Rats. Life Sciences, 79, 2209-22016.

[31]   Grünblatt, E., Salkovic-Petrisic, M., Osmanovic, J., Riederer, P. and Hoyer, S. (2007) Brain Insulin System Dysfunction in Streptozotocin Intracerebroventricularly Treated Rats Generates Hyperphosphorylated Tau Protein. Journal of Neurochemistry, 101, 757-770.

[32]   Salkovic-Petrisic, M., Tribl, F., Schmidt, M., Hoyer, S. and Riederer, P. (2006) Alzheimer-Like Changes in Protein Kinase B and Glycogen Synthase Kinase-3 in Rat Frontal Cortex and Hippocampus after Damage to the Insulin Signalling Pathway. Journal of Neurochemistry, 96, 1005-1015.

[33]   Salkovic-Petrisic, M., Osmanovic, J., Grünblatt, E., Riederer, P. and Hoyer, S. (2009) Modeling Sporadic Alzheimer’s Disease, the Insulin Resistant Brain State Generates Multiple Long-Term Morphobiological Abnormalities Including Hyperphosphorylated Tau Protein and Amyloid-Beta. Journal of Alzheimer’s Disease, 18, 729-750.

[34]   Salkovic-Petrisic, M., Knezovic, A., Siegfred, H. and Riederer, P. (2013) What Have We Learned from the Streptozotocin-Induced Animal Model of Sporadic Alzhei mer’s Disease, about the Therapeutic Strategies in Alzheimer’s Research. Journal of Neural Transmission, 120, 233-252.

[35]   Meneses, A. (2003) A Pharmacological Analysis of an Associative Learning Task, 5-HT(1) to 5-HT(7) Receptor Subtypes Function on a Pavlovian/Instrumental a Auto-shaped Memory. Learning & Memory, 5, 363-372.

[36]   Meneses, A. (2002) Tianeptine, 5-HT Uptake Sites and 5-HT (1-7) Receptors Modulate Memory Formation in an Autoshaping Pavlovian/Instrumental Task. Neuroscience & Biobehavioral Reviews, 26, 309-319.

[37]   Meneses, A. (2007) Do Serotonin1-7 Receptors Modulate Short and Long-Term Memory? Neurobiology of Learning and Memory, 87, 561-572.

[38]   Ponce-Lopez, T., Liy-Sameron, G., Hong, E. and Meneses, A. (2011) Lithium, Phenserine, Memantine and Pioglitazone Reverse Memory Deficit and Restore Phospho-GSK3β Decreased in Hippocampus in Intracerebroventricular Streptozotocin Induced Memory Deficit Model. Brain Research, 1426, 73-85.

[39]   Bradford, M.M. (1976) A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding. Analytical Biochemistry, 7, 248-254.

[40]   Kurien, B.T. and Scofield, R.H. (2003) Protein Blotting, a Review. Journal of Immunological Methods, 274, 1-15.

[41]   Kurien, B.T. and Scofield, R.H. (2006) Western Blotting. Methods, 38, 283-293.

[42]   Baskin, D.G., Figlewicz, D.P., Woods, S.C., Porte, D. and Dorsa, D.M. (1987) Insulin in the Brain. Annual Review of Physiology, 49, 335-347.

[43]   Zhao, W., Chen, H., Xu, H., Moore, E., Meiri, N., Quon, M.J. and Alkon, D.L. (1999) Brain Insulin Receptors and Spatial Memory. Correlated Changes in Gene Expression, Tyrosine Phosphorylation, and Signaling Molecules in the Hippocampus of Water Maze Trained Rats. The Journal of Biological Chemistry, 274, 34893-34902.

[44]   Zhao, W.Q. and Alkon, D.L. (2001) Role of Insulin and Insulin Receptor in Learning and Memory. Molecular and Cellular Endocrinology, 177, 125-134.

[45]   Agrawal, R., Tyagi, E., Shukla, S. and Nath, C. (2009) A Study of Brain Insulin Receptors, AChE Activity and Oxidative Stress in Rat Model of ICV STZ Induced Dementia. Neuropharmacology, 56, 779-787.

[46]   Benedict, C., Brooks, S.J., Kullberg, J., Burgos, J., Kempton, M.J., Nordenskjold, R., Nylander, R., Kilander, L., Craft, S., Larsson, E.-M., Johansson, L., Ahlström, H., Lind, L. and Schiöth, H.B. (2012) Impaired Insulin Sensitivity as Indexed by the HOMA Score Is Associated with Deficits in Verbal Fluency and Temporal Lobe Gray Matter Volume in the Elderly. Diabetes Care, 35, 488-494.

[47]   Crane, P.K., Walker, R., Hubbard, R.A., Li, G., Nathan, D.M., Zheng, H., Haneuse, S., Craft, S., Montine, T.J., Kahn, S.E., McCormick, W., McCurry, S.M., Bowen, J.D. and Larson, E.B. (2013) Glucose Levels and Risk of Dementia. The New England Journal of Medicine, 369, 540-548.

[48]   Craft, S., Baker, L.D., Montine, T.J., Minoshima, S., Watson, G.S., Claxton, A., Arbuckle, M., Callaghan, E., Tsai, R.P., Plymate, P.S., Green, J., Leverenz, D. and Cross, B.G. (2012) Intranasal Insulin Therapy for Alzheimer Disease and Amnestic mild Cognitive Impairment, a Pilot Clinical Trial. Archives of Neurology, 69, 29-38.

[49]   Gong, C.X. and Iqbal, K. (2008) Hyperphosphorylation of Microtubule-Associated Protein Tau, a Promising Therapeutic Target for Alzheimer Disease. Current Medicinal Chemistry, 15, 2321-2328.

[50]   Gong, C.X., Grundke-Iqbal, I. and Iqbal, K. (1994) Dephosphorylation of Alzheimer’s Disease Abnormally Phosphorylated Tau by Protein Phosphatase-2A. Neuroscience, 61, 765-772.

[51]   Lichtenberg-Kraag, B., Wille, H., Gustke, N. and Mandelkow, E. (1993) Microtubule-Associated Protein Tau, Paired Helical Filaments, and Phosphorylation. Annals of the New York Academy of Sciences, 695, 209-216.

[52]   Mandelkow, E.M. and Mandelkow, E. (1994) Tau Protein and Alzheimer’s Disease. Neurobiology of Aging, 15, 85-86.

[53]   Mandelkow, E.M. and Mandelkow, E. (1998) Tau in Alzheimer’s Disease. Trends in Cell Biology, 8, 425-427.

[54]   Goedert, M., Spillantini, M.G., Jakes, R., Rutherford, D. and Crowther, R.A. (1989) Multiple Isoforms of Human Microtubule-Associated Protein Tau, Sequences and Localization in Neurofibrillary Tang Les of Alzheimer’s Disease. Neuron, 3, 519-526.

[55]   Goedert, M., Jakes, R., Crowther, R.A., Cohen, P., Vanmechelen, E., Vandermeeren, M. and Cras, P. (1994) Epitope Mapping of Monoclonal Antibodies to the Paired Helical Filaments of Alzheimer’s Disease, Identification of Phosphorylation Sites in Tau Protein. Biochemical Journal, 301, 871-877.

[56]   Seubert, P., Mawal-Dewan, M., Barbour, R., Jakes, R., Goedert, M., Johnson, G.V., Litersky, J.M., Schenk, D., Lieberburg, I., Trojanowski, J.Q. and Lee, V.M.-Y. (1995) Detection of Phosphorylated Ser262 in Fetal Tau, Adult Tau, and Paired Helical Filament Tau. The Journal of Biological Chemistry, 270, 18917-18922.

[57]   Hong, M. and Lee, V.M.-Y. (1997) Insulin and Insulin-Like Growth Factor-1 Regulate Tau Phosphorylation in Cultured Human Neurons. The Journal of Biological Chemistry, 272, 19547-19553.

[58]   Lesort, M., Jope, R.S. and Johnson, G.V. (1999) Insulin Transiently Increases Tau Phosphorylation, Involvement of Glycogen Synthase Kinase-3beta and Fyn Tyrosine Kinase. Journal of Neurochemistry, 72, 576-584.

[59]   Lesort, M. and Johnson, G.V. (2000) Insulin-Like Growth Factor-1 and Insulin Mediate Transient Site-Selective Increases in Tau Phosphorylation in Primary Cortical Neurons. Neuroscience, 99, 305-316.

[60]   Johnston, A.M., Pirola, L. and Van Obberghen, E. (2003) Molecular Mechanisms of Insulin Receptor Substrate Protein-Mediated Modulation of Insulin Signaling. FEBS Letters, 546, 32-36.

[61]   Cross, D.A.E., Alessi, D.R., Cohen, P., Andjelkovich, M. and Hemmings, B.A. (1995) Inhibition of Glycogen Synthase Kinase-3 by Insulin Mediated Protein Kinase. Nature, 378, 785-789.

[62]   Ishiguro, K., Shiratsuchi, A., Sato, S., Omor, I.A., Arioka, M., Kobayashi, S. and Uchida, T. (1999) Glycogen Synthase Kinase 3-Beta Is Identical to Tau Protein Kinase I Generating Several Epitopes of Paired Helical Filaments. FEBS Letters, 325, 167-172.

[63]   Avila, J., Lucas, J.J., Perez, M. and Hernandez, F. (2004) Role of Tau Protein in Both Physiological and Pathological Conditions. Physiological Reviews, 54, 361-381.

[64]   Takashima, A. (2006) GSK-3 Is Essential in the Pathogenesis of Alzheimer’s Disease. Journal of Alzheimer’s Disease, 9, 309-317.

[65]   Mu-oz-Monta-o, J.R., Moreno, F.J., Avila, J. and Diaz-Nido, J. (1997) Lithium Inhibits Alzheimer’s Disease-Like Tau Protein Phosphorylation in Neurons. FEBS Letters, 411, 183-188.

[66]   Lovestone, S., Reynolds, C.H., Latimer, D., Davis, D.R., Anderton, B.H., Gallo, J.M., Hanger, D., Mulot, S., Marquardt, B. and Stabel, S. (1994) Alzheimer’s Disease-Like Phosphorylation of the Microtubule-Associated Protein Tau by Glycogen Synthase Kinase-3 in Transfected Mammalian Cells. Current Biology, 4, 1077-1086.

[67]   Liu, S.J., Zhang, A.H., Li, H.L., Wang, Q., Deng, H.M., Netzer, W.J., Xu, H. and Wang, J.Z. (2003) Overactivation of Glycogen Synthase Kinase-3 by Inhibition of Phosphoinositol-3 Kinase and Protein Kinase C Leads to Hyperphosphorylation of Tau and Impairment of Spatial Memory. Journal of Neurochemistry, 87, 1333-1344.

[68]   Hernandez, F., Borrell, J., Guaza, C., Avila, J. and Lucas, J.J. (2002) Spatial Learning Deficit in Transgenic Mice That Conditionally Over-Express GSK-3beta in the Brain But Do Not form Tau Filaments. Journal of Neurochemistry, 83, 1529-1533.

[69]   Sontag, E., Nunbhakdi-Craig, V., Lee, G., Brandt, R., Kamibayashi, C., Kuret, J., White III, C.L., Mumby, M.C. and Bloom, G.S. (1999) Molecular Interactions among Protein Phosphatase 2A, Tau, and Microtubules. Implications for the Regulation of Tau Phosphorylation and the Development of Tauopathies. The Journal of Biological Chemistry, 274, 25490-25498.

[70]   Bennecib, M., Gong, C.-X., Grundke-Iqbal, I. and Iqbal, K. (2000) Role of Protein Phosphatase-2A and -1 in the Regulation of GSK-3, cdk5 and cdc2 and the Phosphorylation of Tau in Rat Forebrain. FEBS Letters, 485, 87-93.

[71]   Gong, C.-X., Singh, T.J., Grundke-Iqbal, I. and Iqbal, K. (1993) Phosphoprotein Phosphatase Activities in Alzheimer Disease Brain. Journal of Neurochemistry, 61, 921-927.

[72]   Gong, C.X., Shaikh, S., Wang, J.Z., Zaidi, T., Grundke-Iqbal, I. and Iqbal, K. (1995) Phosphatase Activity toward Abnormally Phosphorylated Tau, Decrease in Alzheimer Disease Brain. Journal of Neurochemistry, 65, 732-738.

[73]   Vogelsberg-Ragaglia, V., Schuck, T., Trojanowski, J.Q. and Lee, V.M. (2001) PP2A mRNA Expression Is Quantitatively Decreased in Alzheimer’s Disease Hippocampus. Experimental Neurology, 168, 402-412.

[74]   Liu, R. and Tian, Q. (2009) Protein Phosphatase 2A, a Key Player in Alzheimer’s Disease. Frontiers of Medicine in China, 3, 8-12.

[75]   Kamat, P.K., Rai, S., Swarnkar, S., Shukla, R., Ali, S., Najmi, A.K. and Nath, C. (2013) Okadaic Acid-Induced Tau Phosphorylation in Rat Brain, Role of NMDA Receptor. Neuroscience, 238, 97-113.