The Links between Brain Insulin Resistance and Alzheimer’s Disease
Type 2 Diabetes (T2DM) and Alzheimer's disease (AD) are two main health problems influencing millions of people in the world. Neuron loss and synaptic impairment that interfere with cognition and memory cause for the behavioral indications of AD. While it is now accepted that insulin has central neuromodulatory purpose, it was contemplated for many years that brain is insusceptible to insulin, involving its function in memory and learning, which are impaired in AD. The common characteristics of both AD and T2D are impaired insulin signaling, oxidative stress, the excitation of inflammatory pathways and unqualified glucose metabolism. This review summarizes how the recognition of these mechanisms may lead to the development of alternative therapeutic approaches. Here we summarize how the recognition of these mechanisms may lead to the development of alternative therapeutic approaches.
Digital Object Identifier (DOI): doi.org/10.5281/zenodo.2571827Procedia APA BibTeX Chicago EndNote Harvard JSON MLA RIS XML ISO 690 PDF Downloads 696
 Jack CR Jr1, Albert MS, Knopman DS, McKhann GM, Sperling RA, Carrillo MC, Thies B, Phelps CH, “Introduction to the recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease”, Alzheimers Dement, 2011, pp. 257-62.
 Sperling, Reisa A., Paul S. Aisen, Laurel A. Beckett, David A. Bennett, Suzanne Craft, Anne M. Fagan, Takeshi Iwatsubo et al. "Toward defining the preclinical stages of Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease." Alzheimer's & dementia 7, no. 3, 2011, pp. 280-92.
 Van Es MA, van den Berg LH, "Alzheimer’s disease beyond APOE", Nat Genet, 2009, pp. 1047-76.
 Akter K, Lanza EA, Martin SA, Myronyuk N, Rua M, Raffa RB. “Diabetes mellitus and Alzheimer’s disease: shared pathology and treatment", Br J Clin Pharmacol, 2011, pp. 365-76.
 de la Monte SM1, Wands JR, "Alzheimer’s disease is type 3 diabetes: evidence reviewed", J Diabetes Sci Technol, 2008, pp. 1101-13.
 Ott A, Stolk RP, van Harskamp F, Pols HA, Hofman A, Breteler MM. "Diabetes mellitus and the risk of dementia: the Rotterdam Study," Neurology , vol. 53, 1999, pp. 1937-42.
 Huang CC, Chung CM, Leu HB, Lin LY, Chiu CC, Hsu CY, Chiang CH, Huang PH, Chen TJ, Lin SJ, Chen JW, Chan WL, "Diabetes mellitus and the risk of Alzheimer's disease: a nationwide population-based study", PLoS One, vol. 9, 2014, pp. 80795.
 Ohara T, Doi Y, Ninomiya T, Hirakawa Y, Hata J, Iwaki T, Kanba S, Kiyohara Y, "Glucose tolerance status and risk of dementia in the community: the Hisayama Study", Neurology, vol. 77, 2011, pp. 1126-34.
 Cha DS, Carvalho AF, Rosenblat JD, Ali MM, McIntyre RS, "Major depressive disorder and type II diabetes mellitus: mechanisms underlying risk for Alzheimer's disease", CNS Neurol. Disord. Drug Targets, vol. 13, 2014, pp. 1740-49.
 Crane PK, Walker R, Hubbard RA, et al, "Glucose levels and risk of dementia", N. Engl. J. Med, vol. 369, 2013, pp. 540-48.
 Kerti L, Witte AV, Winkler A, Grittner U, Rujescu D, Flöel A, "Higher glucose levels associated with lower memory and reduced hippocampal microstructure", Neurology, vol. 81, 2013, pp. 1746-52.
 Baker LD, Cross DJ, Minoshima S, Belongia D, Watson GS, Craft S, "Insulin resistance and Alzheimer-like reductions in regional cerebral glucose metabolism for cognitively normal adults with prediabetes or early type 2 diabetes", Arch.Neurol, vol. 68, 2011, pp. 51-57.
 T. Matsuzaki, K. Sasaki, Y. Tanizaki, J. Hata, K. Fujimi, Y. Matsui, A. Sekita, S.O. Suzuki, S. Kanba, Y. Kiyohara, T. Iwaki, "Insulin resistance is associated with the pathology of Alzheimer disease: The Hisayama study", Neurology , vol. 75, 2010, pp. 764-70.
 Butterfield, D. Allan, Fabio Di Domenico, and Eugenio Barone, "Elevated risk of type 2 diabetes for development of Alzheimer disease: a key role for oxidative stress in brain." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease 1842, no. 9, 2014, pp. 1693-1706.
 Bonadonna RC, De Fronzo RA, "Glucose metabolism in obesity and type 2 diabetes", Diabète métabolisme, vol. 17, 1991, pp. 112-35.
 Chiung‐Chun Huang, Cheng‐Che Lee, Kuei‐Sen Hsu, "An investigation into signal transduction mechanisms involved in insulin-induced long-term depression in the CA1 region of the hippocampus", J. Neurochem, vol. 89, 2004, pp. 217-31.
 Lee, Cheng-Che, Chiung-Chun Huang, Mei-Ying Wu, and Kuei-Sen Hsu, "Insulin stimulates postsynaptic density-95 protein translation via the phosphoinositide 3-kinase-Aktmammalian target of rapamycin signaling pathway", J. Biol. Chem., vol. 280, 2005, pp. 18543-50.
 WQ Zhao, H Chen, MJ Quon, DL Alkon, "Insulin and the insulin receptor in experimental models of learning and memory", Eur. J. Pharmacol, vol. 490, 2004, pp. 71-81.
 Brands, Augustina MA, Geert Jan Biessels, Edward HF De Haan, L. Jaap Kappelle, and Roy PC Kessels, "The effects of type 1 diabetes on cognitive performance: a meta-analysis", Diabetes Care, vol. 28, 2005, pp. 726-35.
 Steen, Eric, Benjamin M. Terry, Enrique J Rivera, Jennifer L. Cannon, Thomas R. Neely, Rose Tavares, X. Julia Xu, Jack R. Wands, and Suzanne M. de la Monte, " Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease is this type 3 diabetes", J. Alzhimers Dis., vol. 7, 2005, pp. 63-80.
 S. Craft, "Alzheimer disease: insulin resistance and AD dextending the translational path", Nat. Rev. Neurol., vol. 8, 2012, pp. 360-2.
 Bomfim, Theresa R., Leticia Forny-Germano, Luciana B. Sathler, Jordano Brito-Moreira, Jean-Christophe Houzel, Helena Decker, Michael A. Silverman et al. "An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease-associated Ab oligomers," J. Clin. Invest, vol. 122, 2012, pp. 1339-53.
 Lourenco, Mychael V., Julia R. Clarke, Rudimar L. Frozza, Theresa R. Bomfim, Letícia Forny-Germano, André F. Batista, Luciana B. Sathler et al. "TNF-alpha mediates PKR-dependent memory impairment and brain IRS-1 inhibition induced by Alzheimer’s beta-amyloid oligomers in mice and monkeyes", cell metab, vol. 18, 2013, pp. 831-43.
 Takeda, Shuko, Naoyuki Sato, Kozue Uchio-Yamada, Kyoko Sawada, Takanori Kunieda, Daisuke Takeuchi, Hitomi Kurinami, Mitsuru Shinohara, Hiromi Rakugi, and Ryuichi Morishita, "Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and Aβ deposition in an Alzheimer mouse model with diabetes", Proceedings of the National Academy of Sciences USA, 2010, pp.7036-7041.
 X Sun, K Bromley‐Brits, W Song, "Regulation of beta-site APP cleaving enzyme 1 gene expression and its role in Alzheimer’s disease", J Neurochem , vol. 120, 2012, pp. 62-70.
 G. Bloom, "Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis", JAMA neurol, vol. 71, 2014, pp. 505-8.
 M Suzanne, "Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease", Drugs, vol. 72, 2012, pp. 49-66.
 Talbot, Konrad, Hoau-Yan Wang, Hala Kazi, Li-Ying Han, Kalindi P. Bakshi, Andres Stucky, Robert L. Fuino et al. "Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline", J Clin Invest, vol. 122, 2012, pp. 1316-38.
 T Arendt, MK Brückner, B Mosch, A Lösche, "Selective cell death of hyperploid neurons in Alzheimer's disease", Am. J. Pathol., vol. 177, 2010, pp. 15-20.
 S. Craft, "Insulin resistance and Alzheimer's disease pathogenesis: potential mechanisms and implications for treatment", Curr. Alzheimer Res., vol. 4, 2007, pp. 147-152.
 Z Cheng, Y Tseng, MF White, "Insulin signaling meets mitochondria in metabolism", Trends Endocrinol Metab, vol. 21, 2010, pp. 589-98.
 MF White, "Insulin signaling in health and disease", Science, vol. 302, 2003, pp. 1710-1.
 Goldstein, Barry J., Anna Bittner-Kowalczyk, Morris F. White, and Mark Harbeck, "Tyrosine dephosphorylation and deactivation of insulin receptor substrate-1 by proteintyrosine phosphatase 1B. Possible facilitation by the formation of a ternary complex with the GRB2 adaptor protein", J. Biol. Chem., vol. 275, 2000, pp. 4283-9.
 Adamo M, Raizada MK, LeRoith D., “Insulin and insulin-like growth factor receptors in the nervous system”, Mol Neurobiol, 1989, pp. 71-100.
 Baskin, Denis G., Dianne Figlewicz Lattemann, Randy J. Seeley, Stephen C. Woods, Daniel Porte Jr, and Michael W. Schwartz, " Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight", Brain Res, vol. 848, 1999, pp. 114-23.
 G. Ahmadian, W. Ju, L. Liu, M. Wyszynski, S. Hyoung Lee, A. W. Dunah, C. Taghibiglou, Y. Wang, J. Lu, T. P. Wong, M. Sheng, and Y. T. Wang, “Tyrosine phosphorylation of GluR2 is required for insulin stimulated AMPA receptor endocytosis and LTD”, EMBO J , 2004, pp. 1040-50.
 WQ Zhao, DL Alkon, "Role of insulin and insulin receptor in learning and memory," Mol Cell Endocrinol, vol. 177, 2001, pp. 125-34.
 Havrankova, J., Roth, J., Brownstein, M., “Insulin receptors are widely distributed in the central nervous system of the rat”, Nature 272, no. 5656, 1978, pp. 827.
 M. Salkovic-Petrisic, S Hoyer "Central Insulin Resistance as a Trigger for Sporadic Alzheimer-like Pathology: An Experimental Approach", Springer, 2007, pp. 217-33.
 Rani, Vanita, Rahul Deshmukh, Priya Jaswal, Puneet Kumar, and Jitender Bariwal, "Alzheimer's disease: Is this a brain specific diabetic condition", physiology and behavior, 2016, pp. 259-267.
 Banks, William A., Shinya Dohgu, Jessica L. Lynch, Melissa A. Fleegal-DeMotta, Michelle A. Erickson, Ryota Nakaoke, and Than Q. Vo, "Nitric oxide isoenzymes regulate lipopolysaccharide-enhanced insulin transport across the blood-brain barrier", Endocrinology, vol. 149, 2008, pp. 1514-23.
 WA Banks, JB Jaspan, W Huang, AJ Kastin, "Transport of insulin across the blood-brain barrier: saturability at euglycemic doses of insulin", Peptides, vol. 18, 1997, pp. 1423-29.
 W. Banks, "The source of cerebral insulin," Eur. J. Pharmacol, 2004.
 Schechter, Ruben, and Michael Abboud. "Neuronal synthesized insulin roles on neural differentiation within fetal rat neuron cell cultures", Developmental Brain Research, 2001, pp. 41-49.
 Pang, Yi, Shuying Lin, Camilla Wright, Juying Shen, Kathleen Carter, Abhay Bhatt, and L-W. Fan, "Intranasal insulin protects against substantia nigra dopaminergic neuronal loss and alleviates motor deficits induced by 6-OHDA in rats", Neuroscience, vol. 318, 2016, pp. 157-65.
 Cardoso, Susana, Sónia Correia, Renato X. Santos, Cristina Carvalho, Maria S. Santos, Catarina R. Oliveira, George Perry, Mark A. Smith, Xiongwei Zhu, and Paula I. Moreira, "Insulin is a two-edged knife on the brain", J. Alzheimer’s Dis., vol. 18, 2009, pp. 483-507.
 D Dávila, I Torres-Aleman, "Neuronal death by oxidative stress involves activation of FOXO3 through a two-arm pathway that activates stress kinases and attenuates insulin-like growth factor I signaling", Mol. Biol. Cell , vol. 19, 2008, pp. 2014-25.
 F.G. De Felice, "Alzheimer's disease and insulin resistance: translating basic science into clinical applications", J. Clin. Invest, vol. 123, 2013, pp. 531-9.
 MF Gregor, GS Hotamisligil, "Inflammatory mechanisms in obesity," Annu Rev Immunol, vol. 29, 2011, pp. 415-45.
 Ledo, J. H., E. P. Azevedo, J. R. Clarke, F. C. Ribeiro, C. P. Figueiredo, D. Foguel, F. G. De Felice, and S. T. Ferreira, "Amyloid-β oligomers link depressive-like behavior and cognitive deficits in mice", Molecular psychiatry, vol 18, no. 10, 2013, pp. 1053.
 Yoon, Sung Ok, Dong Ju Park, Jae Cheon Ryu, Hatice Gulcin Ozer, Chhavy Tep, Yong Jae Shin, Tae Hee Lim et al. "JNK3 perpetuates metabolic stress induced by Aβ peptides", Neuron, vol 75, no. 5, 2012, pp. 824-37.
 G.N. Brito, "Exercise and cognitive function: a hypothesis for the association of type II diabetes mellitus and Alzheimer's disease from an evolutionary perspective," Diabetol. Metab. Syndr, 2009.
 N Henneberg, S Hoyer, "Desensitization of the neuronal insulin receptor: a new approach in the etiopathogenesis of late-onset sporadic dementia of the Alzheimer type (SDAT)", Arch Gerontol Geriatr, vol. 21, 1995, pp. 63-74.
 Rivera, Enrique J., Alison Goldin, Noah Fulmer, Rose Tavares, Jack R. Wands, and Suzanne M. de la Monte, "Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine", Journal of Alzheimer's Disease, vol 8, no. 3, 2005, pp. 247-268.
 Frölich, L., D. Blum-Degen, H-G. Bernstein, S. Engelsberger, J. Humrich, S. Laufer, D. Muschner et al. "Brain insulin and insulin receptors in aging and sporadic Alzheimer's disease", Journal of neural transmission, vol 105, no. 4-5, 1998, pp. 423-38.
 Lester-Coll, Nataniel, Enrique J. Rivera, Stephanie J. Soscia, Kathryn Doiron, Jack R. Wands, and Suzanne M. de la Monte, "Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease", Journal of Alzheimer's Disease, vol 9, no. 1, 2006, pp. 13-33.
 A.D. Bolzán, M.S. Bianchi, “Genotoxicity of streptozotocin”, Mutat. Res., 2002, pp. 121-34.
 T. Szkudelski, "The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas", Physiol. Res., 2001, pp. 537-46.
 J. M. Suzanne, "Alzheimer's disease is type 3 diabetes—evidence reviewed," Journal of Diabetes Science and Technology, 2008, pp. 1101-13.
 Grünblatt, Edna, Melita Salkovic‐Petrisic, Jelena Osmanovic, Peter Riederer, and Siegfried Hoyer, "Brain insulin system dysfunction in streptozotocin intracerebroventricularly treated rats generates hyperphosphorylated tau protein", Journal of neurochemistry, vol 101, no. 3, 2007, pp. 757-70.
 Sato, Naoyuki, Shuko Takeda, Kozue Uchio-Yamada, Hironori Ueda, Tomomi Fujisawa, Hiromi Rakugi, and Ryuichi Morishita, "Role of insulin signaling in the interaction between Alzheimer disease and diabetes mellitus: a missing link to therapeutic potential", Current aging science, vol 4, no. 2, 2011, pp. 118-27.
 Zhao, Wei-Qin, Fernanda G. De Felice, Sara Fernandez, Hui Chen, Mary P. Lambert, Michael J. Quon, Grant A. Krafft, and William L. Klein, "Amyloid beta oligomers induce impairment of neuronal insulin receptors", The FASEB Journal, vol 22, no. 1, 2008, pp. 246-60.
 Hirosumi, Jiro, Gürol Tuncman, Lufen Chang, Cem Z. Görgün, K. Teoman Uysal, Kazuhisa Maeda, Michael Karin, and Gökhan S. Hotamisligil, "A central role for JNK in obesity and insulin resistance", Nature, vol 420, no. 6913, 2002, pp. 333.
 Bhaskar, Kiran, Nicole Maphis, Guixiang Xu, Nicholas H. Varvel, Olga N. Kokiko-Cochran, Jason P. Weick, Susan M. Staugaitis et al. "Microglial derived tumor necrosis factor-α drives Alzheimer's disease-related neuronal cell cycle events", Neurobiology of disease, vol 62, 2014, pp. 273-85.
 Carrero, I., M. R. Gonzalo, B. Martin, J. M. Sanz-Anquela, J. Arevalo-Serrano, and A. Gonzalo-Ruiz, "Oligomers of beta-amyloid protein (Aβ1-42) induce the activation of cyclooxygenase-2 in astrocytes via an interaction with interleukin-1beta, tumour necrosis factor-alpha, and a nuclear factor kappa-B mechanism in the rat brain", Experimental neurology, vol 236, no. 2, 2012, pp. 215-27.
 Wang, Hoau-Yan, Kalindi Bakshi, Maya Frankfurt, Andres Stucky, Marissa Goberdhan, Sanket M. Shah, and Lindsay H. Burns, "Reducing amyloid-related Alzheimer's disease pathogenesis by a small molecule targeting filamin A", Journal of Neuroscience, vol 32, no. 29, 2012, pp.9773-84.
 Espinosa, Ana, Montserrat Alegret, Sergi Valero, Georgina Vinyes-Junqué, Isabel Hernández, Ana Mauleón, Maitée Rosende-Roca et al. "A longitudinal follow-up of 550 mild cognitive impairment patients: evidence for large conversion to dementia rates and detection of major risk factors involved", Journal of Alzheimer's Disease, vol 34, no. 3, 2013, pp.769-80.
 Clark, Ian, Craig Atwood, Richard Bowen, Gilberto Paz-Filho, and Bryce Vissel, "Tumor necrosis factor-induced cerebral insulin resistance in Alzheimer's disease links numerous treatment rationales", Pharmacological reviews, vol 64, no. 4, 2012, pp. 1004-26.
 Donath, Marc Y., and Steven E. Shoelson, "Type 2 diabetes as an inflammatory disease", Nature Reviews Immunology, vol 11, no. 2, 2011, pp. 98.
 Najem, Dema, Michelle Bamji-Mirza, Nina Chang, Qing Yan Liu, and Wandong Zhang, "Insulin resistance, neuroinflammation, and Alzheimer’s disease." Reviews in the Neurosciences, vol 25, no. 4, 2014, pp. 509-25.
 Herder, C., T. Illig, W. Rathmann, S. Martin, B. Haastert, S. Müller-Scholze, R. Holle et al. "Inflammation and type 2 diabetes: results from KORA Augsburg," Das Gesundheitswesen, vol 67, no. S 01, 2005, pp. 115-21.
 Herder, Christian, Eric J. Brunner, Wolfgang Rathmann, Klaus Strassburger, Adam G. Tabák, Nanette C. Schloot, and Daniel R. Witte, "Elevated levels of the anti-inflammatory interleukin-1 receptor antagonist precede the onset of type 2 diabetes: The Whitehall II study", Diabetes care, vol 32, no. 3, 2009, pp. 421-3.
 Ehses, Jan A., Aurel Perren, Elisabeth Eppler, Pascale Ribaux, John A. Pospisilik, Ranit Maor-Cahn, Xavier Gueripel et al. "Increased number of islet-associated macrophages in type 2 diabetes", Diabetes, vol 56, no. 9, 2007, pp. 2356-70.
 Blalock, E. M., K-C. Chen, A. J. Stromberg, C. M. Norris, I. Kadish, S. D. Kraner, N. M. Porter, and P. W. Landfield, "Harnessing the power of gene microarrays for the study of brain aging and Alzheimer's disease: statistical reliability and functional correlation", Ageing research reviews, vol 4, no. 4, 2005, pp. 481-512.
 Katsel, Pavel L., Kenneth L. Davis, and Vahram Haroutunian, "Large-scale microarray studies of gene expression in multiple regions of the brain in schizophrenia and Alzheimer's disease", 2005, pp. 41-82.
 Wyss-Coray, Tony, "Inflammation in Alzheimer disease: driving force, bystander or beneficial response", Nature medicine, vol 12, no. 9, 2006, pp. 1005.
 Szekely, Christine A., Jennifer E. Thorne, Peter P. Zandi, Mats Ek, Erick Messias, John CS Breitner, and Steven N. Goodman, "Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease: a systematic review", Neuroepidemiology, vol 23, no. 4, 2004, pp. 159-69.
 Wullschleger, Stephan, Robbie Loewith, and Michael N. Hall, "TOR signaling in growth and metabolism", cell 124, no. 3, 2006, pp. 471-84.
 Zoncu, Roberto, Alejo Efeyan, and David M. Sabatini, "mTOR: from growth signal integration to cancer, diabetes and ageing", Nature reviews Molecular cell biology, vol 12, no. 1, 2011, pp. 21.
 Loewith, Robbie, Estela Jacinto, Stephan Wullschleger, Anja Lorberg, José L. Crespo, Débora Bonenfant, Wolfgang Oppliger, Paul Jenoe, and Michael N. Hall, "Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control", Molecular cell, vol 10, no. 3, 2002, pp. 457-68.
 Ben-Sahra, Issam, Gerta Hoxhaj, Stéphane JH Ricoult, John M. Asara, and Brendan D. Manning, "mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle", Science, vol 351, no. 6274, 2016, pp. 728-33.
 Hresko, Richard C., and Mike Mueckler, "mTOR• RICTOR is the Ser473 kinase for Akt/protein kinase B in 3T3-L1 adipocytes", Journal of Biological Chemistry, vol 280, no. 49, 2005, pp. 40406-16.
 Norambuena, Andrés, Horst Wallrabe, Lloyd McMahon, Antonia Silva, Eric Swanson, Shahzad S. Khan, Daniel Baerthlein et al. "mTOR and neuronal cell cycle reentry: how impaired brain insulin signaling promotes Alzheimer's disease." Alzheimer's & Dementia, vol 13, no. 2, 2017, pp. 152-67.
 Pei, Jin-Jing, Cecilia Björkdahl, Haiyan Zhang, Xinwen Zhou, and Bengt Winblad, "p70 S6 kinase and tau in Alzheimer's disease", Journal of Alzheimer's Disease, vol 14, no. 4, 2008, pp. 385-92.
 Seward, Matthew E., Eric Swanson, Andrés Norambuena, Anja Reimann, J. Nicholas Cochran, Rong Li, Erik D. Roberson, and George S. Bloom, "Amyloid-β signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer's disease", J Cell Sci, 2013, jcs-1125880.
 Hallschmid, M., and B. Schultes, "Central nervous insulin resistance: a promising target in the treatment of metabolic and cognitive disorders", Diabetologia, vol 52, no. 11, 2009, pp. 2264-9.
 Bosco, Domenico, Antonietta Fava, Massimiliano Plastino, Tiziana Montalcini, and Arturo Pujia, "Possible implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis", Journal of cellular and molecular medicine, vol 15, no. 9, 2011, pp. 1807-21.
 Rapoport, Stanley I., Kimmo Hatanpää, Daniel R. Brady, and Krish Chandrasekaran, "Brain energy metabolism, cognitive function and down-regulated oxidative phosphorylation in Alzheimer disease", Neurodegeneration, vol 5, no. 4, 1996, pp. 473-6.
 M. Smith, "Diabetes mellitus and Alzheimer's disease: glycation as a biochemical link," Diabetologia, 1996, p. 247.
 DeFronzo, Ralph A., and Devjit Tripathy, "Skeletal muscle insulin resistance is the primary defect in type 2 diabetes", Diabetes care, vol 32, no. suppl 2, 2009, pp. S157-63.
 A. Nunomura, G. Perry, M. A. Pappolla, R. Wade, K. Hirai, S. Chiba and Mark A, “RNA oxidation is a prominent feature of vulnerable neurons in Alzheimer's disease”, J. Neuroscience, 1999, pp. 1959-64.
 Vincent, Andrea M., James W. Russell, Phillip Low, and Eva L. Feldman, "Oxidative stress in the pathogenesis of diabetic neuropathy", Endocrine reviews, vol 25, no. 4, 2004, pp. 612-28.
 Rösen, P., P. P. Nawroth, Gr King, W. Möller, H‐J. Tritschler, and L. Packer, "The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO‐MCBN, the American Diabetes Association and the German Diabetes Society." Diabetes/metabolism research and reviews, vol 17, no. 3, 2001, pp. 189-212.
 Russell, James W., Alison Berent-Spillson, Andrea M. Vincent, Catherine L. Freimann, Kelli A. Sullivan, and Eva L. Feldman, "Oxidative injury and neuropathy in diabetes and impaired glucose tolerance." Neurobiology of disease, vol 30, no. 3 (2008, pp. 420-9.
 Resende, Rosa, Paula Isabel Moreira, Teresa Proença, Atul Deshpande, Jorge Busciglio, Cláudia Pereira, and Catarina Resende Oliveira, "Brain oxidative stress in a triple-transgenic mouse model of Alzheimer disease." Free Radical Biology and Medicine, vol 44, no. 12, 2008, pp. 2051-7.
 Apelt, Jenny, Marina Bigl, Patrick Wunderlich, and Reinhard Schliebs, "Aging-related increase in oxidative stress correlates with developmental pattern of beta-secretase activity and beta-amyloid plaque formation in transgenic Tg2576 mice with Alzheimer-like pathology." International Journal of Developmental Neuroscience, vol 22, no. 7, 2004, pp. 475-84.
 Jo, Dong-Gyu, Thiruma V. Arumugam, Ha-Na Woo, Jong-Sung Park, Sung-Chun Tang, Mohamed Mughal, Dong-Hoon Hyun et al. "Evidence that γ-secretase mediates oxidative stress-induced β-secretase expression in Alzheimer's disease." Neurobiology of aging, vol 31, no. 6, 2010, pp. 917-25.
 Oda, Akiko, Akira Tamaoka, and Wataru Araki, "Oxidative stress up‐regulates presenilin 1 in lipid rafts in neuronal cells." Journal of neuroscience research, vol 88, no. 5, 2010, pp. 1137-45.
 Reddy, P. Hemachandra, Maria Manczak, Peizhong Mao, Marcus J. Calkins, Arubala P. Reddy, and Ulziibat Shirendeb, "Amyloid-β and mitochondria in aging and Alzheimer's disease: implications for synaptic damage and cognitive decline." Journal of Alzheimer's disease, vol 20, no. s2, 2010, S499-512.
 Sultana, Rukhsana, Debra Boyd-Kimball, H. Fai Poon, Jain Cai, William M. Pierce, Jon B. Klein, William R. Markesbery, Xiao Zhen Zhou, Kun Ping Lu, and D. Allan Butterfield, "Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: a redox proteomics analysis." Neurobiology of aging, vol 27, no. 7, 2006, pp. 918-25.
 Butterfield, D. Allan, Marzia Perluigi, and Rukhsana Sultana, "Oxidative stress in Alzheimer's disease brain: new insights from redox proteomics." European journal of pharmacology, vol 545, no. 1, 2006, pp. 39-50.
 Grundke-Iqbal, Inge, Khalid Iqbal, Yunn-Chyn Tung, Maureen Quinlan, Henryk M. Wisniewski, and Lester I. Binder, "Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology." Proceedings of the National Academy of Sciences 83, no. 13, 1986, pp. 4913-7.
 Iqbal, Khalid, Alejandra del C. Alonso, She Chen, M. Omar Chohan, Ezzat El-Akkad, Cheng-Xin Gong, Sabiha Khatoon et al. "Tau pathology in Alzheimer disease and other tauopathies." Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, vol 1739, no. 2-3, 2005, pp. 198-210.
 Suzanne M., "Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease." Drugs 72, no. 1, 2012, pp. 49-66.
 Calvo-Ochoa, Erika, Karina Hernández-Ortega, Patricia Ferrera, Sumiko Morimoto, and Clorinda Arias, "Short-term high-fat-and-fructose feeding produces insulin signaling alterations accompanied by neurite and synaptic reduction and astroglial activation in the rat hippocampus." Journal of Cerebral Blood Flow & Metabolism, vol 34, no. 6 (2014, pp. 1001-8.
 Ramos-Rodriguez, Juan Jose, Sara Molina-Gil, Oscar Ortiz-Barajas, Margarita Jimenez-Palomares, German Perdomo, Irene Cozar-Castellano, Alfonso Maria Lechuga-Sancho, and Monica Garcia-Alloza, "Central proliferation and neurogenesis is impaired in type 2 diabetes and prediabetes animal models." PLoS One, vol 9, no. 2, 2014, e89229.
 Selkoe, Dennis J., "Resolving controversies on the path to Alzheimer's therapeutics." Nature medicine 17, no. 9, 2011, pp. 1060.
 Cole, Greg M., and Sally A. Frautschy, "The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer’s disease." Experimental gerontology 42, no. 1-2, 2007, pp. 10-21.
 Freiherr, Jessica, Manfred Hallschmid, William H. Frey, Yvonne F. Brünner, Colin D. Chapman, Christian Hölscher, Suzanne Craft, Fernanda G. De Felice, and Christian Benedict, "Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence." CNS drugs, vol 27, no. 7, 2013, pp. 505-14.
 Benedict, Christian, William H. Frey II, Helgi B. Schiöth, Bernd Schultes, Jan Born, and Manfred Hallschmid, "Intranasal insulin as a therapeutic option in the treatment of cognitive impairments." Experimental gerontology, vol 46, no. 2-3, 2011, pp. 112-5.
 Reger, M. A., G. S. Watson, W. H. Frey Ii, L. D. Baker, B. Cholerton, M. L. Keeling, D. A. Belongia et al. "Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype." Neurobiology of aging, vol 27, no. 3, 2006, pp. 451-8.
 Reger, Mark A., G. Watson, Pattie S. Green, Laura D. Baker, Brenna Cholerton, Mark A. Fishel, Stephen R. Plymate et al. "Intranasal insulin administration dose-dependently modulates verbal memory and plasma amyloid-β in memory-impaired older adults." Journal of Alzheimer's disease, vol 13, no. 3, 2008, pp. 323-31.
 Kim, Bhumsoo, and Eva L. Feldman, "Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome." Experimental & molecular medicine, vol 47, no. 3, 2015, e149.
 McIntyre, Roger S., Alissa M. Powell, Oksana Kaidanovich-Beilin, Joanna K. Soczynska, Mohammad Alsuwaidan, Hanna O. Woldeyohannes, Ashley S. Kim, and L. Ashley Gallaugher, "The neuroprotective effects of GLP-1: possible treatments for cognitive deficits in individuals with mood disorders." Behavioural brain research 237, 2013, pp. 164-71.
 Corbett, Anne, James Pickett, Alistair Burns, Jonathan Corcoran, Stephen B. Dunnett, Paul Edison, Jim J. Hagan et al. "Drug repositioning for Alzheimer's disease." Nature Reviews Drug Discovery, vol 11, no. 11, 2012, pp. 833.
 Abbas T, Faivre E, Hölscher C., “Impairment of synaptic plasticity and memory formation in GLP-1 receptor KO mice: interaction between type 2 diabetes and Alzheimer’s disease”, Behav Brain Res, 2009, pp. 265-71.
 Yusta, Bernardo, Laurie L. Baggio, Jennifer L. Estall, Jackie A. Koehler, Dianne P. Holland, Hongyun Li, Danny Pipeleers, Zhidong Ling, and Daniel J. Drucker, "GLP-1 receptor activation improves β cell function and survival following induction of endoplasmic reticulum stress." Cell metabolism, vol 4, no. 5, 2006, pp. 391-406.
 Hunter, Kerry, and Christian Hölscher, "Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis." BMC neuroscience, vol 13, no. 1, 2012, pp. 33.
 Fernanda G. De Felice*, Mychael V. Lourenco, Sergio T. Ferreira, “How does brain insulin resistance develop in Alzheimer’s disease?”, Alzheimer’s & Dementia, vol 10, 2014, pp. S26–32.
 Han, Wei-Na, Christian Hölscher, Li Yuan, Wei Yang, Xiao-Hui Wang, Mei-Na Wu, and Jin-Shun Qi, "Liraglutide protects against amyloid-β protein-induced impairment of spatial learning and memory in rats." Neurobiology of aging, vol 34, no. 2, 2013, pp. 576-88.
 McClean, Paula L., Vadivel Parthsarathy, Emilie Faivre, and Christian Hölscher, "The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer's disease." Journal of Neuroscience, vol 31, no. 17, 2011, pp. 6587-94.
 Kim, Bhumsoo, and Eva L. Feldman, "Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome." Experimental & molecular medicine, vol 47, no. 3, 2015, e149.
 Imfeld, Patrick, Michael Bodmer, Susan S. Jick, and Christoph R. Meier, "Metformin, Other Antidiabetic Drugs, and Risk of Alzheimer's disease: A Population‐Based Case–Control Study." Journal of the American Geriatrics Society, vol 60, no. 5, 2012, pp. 916-21.
 Miller, Benjamin W., Kristine C. Willett, and Alicia R. Desilets, "Rosiglitazone and pioglitazone for the treatment of Alzheimer's disease." Annals of Pharmacotherapy, vol 45, no. 11, 2011, pp. 1416-24.