diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/2072-0351-5842diaendo-8282Research ArticleОбучение и психосоциальные аспектыEducation and psychosociologycal aspectsТаупатия и когнитивные нарушения при экспериментальном сахарном диабетеTauopathy and cognitive impairment in experimental diabetes mellitusМатвееваМария ВладимировнаMatveevaMariia V.

к.м.н.

MD, PhD

matveeva.mariia@yandex.ruСамойловаЮлия ГеннадьевнаSamoiIovaYulia G.

д.м.н., профессор

MD, PhD, Professor

samoilova_y@inbox.ruЖуковаНаталья ГригорьевнаZhukovaNatalia G.

д.м.н., профессор

MD, PhD, Professor

znatali@yandex.ruОлейникОксана АлексеевнаOleynikOksana A.

к.м.н., доцент

MD, PhD, associate professor

oleynikoa@mail.ruРотканкМария АлександровнаRotkankMaria A.

ассистент

assistant lecturer

rotkank.mariya@mail.ru<p>ФГБОУ ВО &laquo;Сибирский государственный медицинский университет&raquo; Минздрава России</p>Россия<p>Siberian State Medical University</p>Russian Federation201710082017203181184Copyright &#x00A9; Матвеева М.В., Самойлова Ю.Г., Жукова Н.Г., Олейник О.А., Ротканк М.А., 20172017Матвеева М.В., Самойлова Ю.Г., Жукова Н.Г., Олейник О.А., Ротканк М.А.Matveeva M.V., SamoiIova Y.G., Zhukova N.G., Oleynik O.A., Rotkank M.A.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/8282

На сегодняшний день сахарный диабет (СД) является наиболее распространенной патологией нарушения обмена веществ, которая проявляется гипергликемией и приводит к сосудистым и когнитивным нарушениям. Механизмы формирования когнитивной дисфункции у пациентов с СД в значительной мере остаются неясными, что усложняет поиски эффективных стратегий предотвращения и лечения деменции. В последнее время учеными обсуждаются вопросы связи СД и болезни Альцгеймера (БА), а именно риски и факторы, запускающие каскад патологических реакций. С одной стороны, пациенты с СД показывают повышенный риск развития БА. Точно так же у пациентов с БА выявляются нарушения функции инсулина и метаболизма глюкозы. Обе эти нозологии имеют общие патофизиологические и биохимические основы, такие как оксидативный стресс, формирование конечных продуктов гликирования, дисрегуляция метаболизма глюкозы, изменение сигнальных путей инсулина. Также известно, что ассоциированный с микротрубочками тау-белок выступает в роли одного из этиологических механизмов развития БА. Приведен обзор основных отечественных и зарубежных данных анализа связи тау-белка и развития когнитивных нарушений при экспериментальном СД.

Currently, diabetes mellitus (DM) is the most common metabolic disorder, which is manifested by hyperglycemia and leads to vascular and cognitive impairment. Mechanisms of cognitive dysfunction in patients with DM remain highly unclear, thus complicating the search for effective strategies for the prevention and treatment of dementia. Recently, scientists have discussed the issues regarding the relationship between DM and Alzheimer’s disease (AD), such as risk factors that trigger the cascade of pathological reactions. Patients with DM show an increased risk of developing AD. Similarly, patients with AD have been shown to have impaired insulin and glucose metabolism. Both these diseases have common nosology, pathology and biochemical basics, including oxidative stress, formation of advanced glycation end products, dysregulation of glucose metabolism and altered insulin signaling pathways. The microtubule-associated tau protein is involved in one of the causative mechanisms underlying the development of AD. We provide an overview of the major domestic and foreign data analyses regarding tau protein and the development of cognitive disorders in experimental DM.

сахарный диабеткогнитивные нарушениятау-белокболезнь Альцгеймераdiabetes mellitus type 1cognitive impairmenttau proteinAlzheimer's diseaseReferencesGoedert M, Wischik CM, Crowther RA, et al. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci.. 1988;85(11):4051-4055. doi: 10.1073/pnas.85.11.4051Goedert M, Wischik CM, Crowther RA, et al. Cloning and sequencing of the cDNA encoding a core protein of the paired helical filament of Alzheimer disease: identification as the microtubule-associated protein tau. Proc. Natl. Acad. Sci.. 1988;85(11):4051-4055. doi: 10.1073/pnas.85.11.4051Rockenstein E, Torrance M, Adame A, et al. Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci. 2007;27(8):1981-1991. doi: 10.1523/JNEUROSCI.4321-06.2007Rockenstein E, Torrance M, Adame A, et al. Neuroprotective effects of regulators of the glycogen synthase kinase-3beta signaling pathway in a transgenic model of Alzheimer's disease are associated with reduced amyloid precursor protein phosphorylation. J Neurosci. 2007;27(8):1981-1991. doi: 10.1523/JNEUROSCI.4321-06.2007Asano T, Fujishiro M, Kushiyama A, et al. Role of Phosphatidylinositol 3-Kinase Activation on Insulin Action and Its Alteration in Diabetic Conditions. Biol Pharm Bull. 2007;30(9):1610-1616. doi: 10.1248/bpb.30.1610Asano T, Fujishiro M, Kushiyama A, et al. Role of Phosphatidylinositol 3-Kinase Activation on Insulin Action and Its Alteration in Diabetic Conditions. Biol Pharm Bull. 2007;30(9):1610-1616. doi: 10.1248/bpb.30.1610Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362(4):329–344. doi: 10.1056/NEJMra0909142Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med. 2010;362(4):329–344. doi: 10.1056/NEJMra0909142El Khoury NB, Gratuze M, Papon MA, et al. Insulin dysfunction and Tau pathology. Front Cell Neurosci. 2014;8:22. doi: 10.3389/fncel.2014.00022El Khoury NB, Gratuze M, Papon MA, et al. Insulin dysfunction and Tau pathology. Front Cell Neurosci. 2014;8:22. doi: 10.3389/fncel.2014.00022Buée L, Bussière T, Buée-Scherrer V, et al. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33(1):95-130. doi: 10.1016/s0165-0173(00)00019-9Buée L, Bussière T, Buée-Scherrer V, et al. Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev. 2000;33(1):95-130. doi: 10.1016/s0165-0173(00)00019-9Боголепова А.Н. Болезнь Альцгеймера и сахарный диабет. Когнитивные нарушения и деменция. // Медицинский совет. – 2015. – №18. – С. 36-40. [Bogolepova AN. Alzheimer’s Disease and diabetes mellitus. Cognitve impairement and dementia. Meditsinskiy sovet. 2015;(18):36-40 (in Russ.)]Боголепова А.Н. Болезнь Альцгеймера и сахарный диабет. Когнитивные нарушения и деменция. // Медицинский совет. – 2015. – №18. – С. 36-40. [Bogolepova AN. Alzheimer’s Disease and diabetes mellitus. Cognitve impairement and dementia. Meditsinskiy sovet. 2015;(18):36-40 (in Russ.)]Пономарёв В.В. Нейродегенеративные заболевания: настоящее и будущее. // Медицинские новости. – 2007. – №5. – С. 23-28. [Ponomaryov VV. Neurodegenerative diseases: Presentand Future. Medicinskie novosti. 2007;(5):23-28 (in Russ.)]Пономарёв В.В. Нейродегенеративные заболевания: настоящее и будущее. // Медицинские новости. – 2007. – №5. – С. 23-28. [Ponomaryov VV. Neurodegenerative diseases: Presentand Future. Medicinskie novosti. 2007;(5):23-28 (in Russ.)]Chen YG. Specific tau phosphorylation sites in hippocampus correlate with impairment of step-down inhibitory avoidance task in rats. Behav Brain Res. 2005;158(2):277-284. doi: 10.1016/j.bbr.2004.09.007Chen YG. Specific tau phosphorylation sites in hippocampus correlate with impairment of step-down inhibitory avoidance task in rats. Behav Brain Res. 2005;158(2):277-284. doi: 10.1016/j.bbr.2004.09.007Le Freche H, Brouillette J, Fernandez-Gomez FJ, et al. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology. 2012;116(4):779-787. doi: 10.1097/ALN.0b013e31824be8c7Le Freche H, Brouillette J, Fernandez-Gomez FJ, et al. Tau phosphorylation and sevoflurane anesthesia: an association to postoperative cognitive impairment. Anesthesiology. 2012;116(4):779-787. doi: 10.1097/ALN.0b013e31824be8c7Wang JZ, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol. 2008;85(2):148-175. doi: 10.1016/j.pneurobio.2008.03.002Wang JZ, Liu F. Microtubule-associated protein tau in development, degeneration and protection of neurons. Prog Neurobiol. 2008;85(2):148-175. doi: 10.1016/j.pneurobio.2008.03.002Tracy TE, Gan L. Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss: Increased levels of acetylated tau blocks the postsynaptic signaling required for plasticity and promotes memory deficits associated with tauopathy. Bioessays. 2017;39(4). doi: 10.1002/bies.201600224Tracy TE, Gan L. Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss: Increased levels of acetylated tau blocks the postsynaptic signaling required for plasticity and promotes memory deficits associated with tauopathy. Bioessays. 2017;39(4). doi: 10.1002/bies.201600224Карпова О.В., Смоленцева И.Г., Амосова Н.А. Реабилитация больных на ранней стадии болезни Паркинсона // Вестник восстановительной медицины. – 2014. – №3. – С. 51-52. [Karpova OV, Smolentseva IG, Amosova NA. The rehabilitation of patients with early Parkinson's disease. Vestnik vosstanovitel'noi meditsiny. 2014;(3): 51-52. (in Russ.)]Карпова О.В., Смоленцева И.Г., Амосова Н.А. Реабилитация больных на ранней стадии болезни Паркинсона // Вестник восстановительной медицины. – 2014. – №3. – С. 51-52. [Karpova OV, Smolentseva IG, Amosova NA. The rehabilitation of patients with early Parkinson's disease. Vestnik vosstanovitel'noi meditsiny. 2014;(3): 51-52. (in Russ.)]Hatch RJ, Wei Y, Xia D, Gotz J. Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment. Acta Neuropathol. 2017;133(5):717-730. doi: 10.1007/s00401-017-1674-1Hatch RJ, Wei Y, Xia D, Gotz J. Hyperphosphorylated tau causes reduced hippocampal CA1 excitability by relocating the axon initial segment. Acta Neuropathol. 2017;133(5):717-730. doi: 10.1007/s00401-017-1674-1Boekhoorn K, Terwel D, Biemans B, et al. Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci. 2006;26(13):3514-3523. doi: 10.1523/JNEUROSCI.5425-05.2006Boekhoorn K, Terwel D, Biemans B, et al. Improved long-term potentiation and memory in young tau-P301L transgenic mice before onset of hyperphosphorylation and tauopathy. J Neurosci. 2006;26(13):3514-3523. doi: 10.1523/JNEUROSCI.5425-05.2006Chu J, Lauretti E, Pratico D. Caspase-3-dependent cleavage of Akt modulates tau phosphorylation via GSK3beta kinase: implications for Alzheimer's disease. Mol Psychiatry. 2017. doi: 10.1038/mp.2016.214Chu J, Lauretti E, Pratico D. Caspase-3-dependent cleavage of Akt modulates tau phosphorylation via GSK3beta kinase: implications for Alzheimer's disease. Mol Psychiatry. 2017. doi: 10.1038/mp.2016.214Иванова С.А., Лосенков И.С., Бохан Н.А. Роль киназы гликогенсинтазы-3 в патогенезе психических расстройств. // Журнал неврологии и психиатрии им. С.С. Корсакова. – 2014. – Т. 114. – №6. – С. 93-100. [Ivanova SA, Losenkov IS, Bohan NA. Role of glycogen synthase-3 kinase in the pathogenesis of psychiatric disorders. Zhurnal nevrologii i psihiatrii im. S.S. Korsakova. 2014;114(6): 93-100 (in Russ.)]Иванова С.А., Лосенков И.С., Бохан Н.А. Роль киназы гликогенсинтазы-3 в патогенезе психических расстройств. // Журнал неврологии и психиатрии им. С.С. Корсакова. – 2014. – Т. 114. – №6. – С. 93-100. [Ivanova SA, Losenkov IS, Bohan NA. Role of glycogen synthase-3 kinase in the pathogenesis of psychiatric disorders. Zhurnal nevrologii i psihiatrii im. S.S. Korsakova. 2014;114(6): 93-100 (in Russ.)]Enman NM, Unterwald EM. Inhibition of GSK3 attenuates amphetamine-induced hyperactivity and sensitization in the mouse. Behavioural Brain Research. 2012;231(1):217-225. doi: 10.1016/j.bbr.2012.03.027Enman NM, Unterwald EM. Inhibition of GSK3 attenuates amphetamine-induced hyperactivity and sensitization in the mouse. Behavioural Brain Research. 2012;231(1):217-225. doi: 10.1016/j.bbr.2012.03.027Saltiel AR. New Perspectives into the Molecular Pathogenesis and Treatment of Type 2 Diabetes. Cell. 2001;104(4):517-529. doi: 10.1016/s0092-8674(01)00239-2Saltiel AR. New Perspectives into the Molecular Pathogenesis and Treatment of Type 2 Diabetes. Cell. 2001;104(4):517-529. doi: 10.1016/s0092-8674(01)00239-2Abbondante S, Baglietto-Vargas D, Rodriguez-Ortiz CJ, et al. Genetic Ablation of Tau Mitigates Cognitive Impairment Induced by Type 1 Diabetes. The American Journal of Pathology. 2014;184(3):819-826. doi: 10.1016/j.ajpath.2013.11.021Abbondante S, Baglietto-Vargas D, Rodriguez-Ortiz CJ, et al. Genetic Ablation of Tau Mitigates Cognitive Impairment Induced by Type 1 Diabetes. The American Journal of Pathology. 2014;184(3):819-826. doi: 10.1016/j.ajpath.2013.11.021Brabley CA, Peineau S, Taghibiglou C, et al. A pivotal role of GSK-3 in synaptic plasticity. Frontiers in Molecular Neuroscience.2012; 5: 16-26.Brabley CA, Peineau S, Taghibiglou C, et al. A pivotal role of GSK-3 in synaptic plasticity. Frontiers in Molecular Neuroscience.2012; 5: 16-26.Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci. 2005;22(8):1942-1950. doi: 10.1111/j.1460-9568.2005.04391.xLiu F, Grundke-Iqbal I, Iqbal K, Gong CX. Contributions of protein phosphatases PP1, PP2A, PP2B and PP5 to the regulation of tau phosphorylation. Eur J Neurosci. 2005;22(8):1942-1950. doi: 10.1111/j.1460-9568.2005.04391.xMalone JI. Diabetic Central Neuropathy: CNS Damage Related to Hyperglycemia. Diabetes. 2016;65(2):355-357. doi: 10.2337/dbi15-0034Malone JI. Diabetic Central Neuropathy: CNS Damage Related to Hyperglycemia. Diabetes. 2016;65(2):355-357. doi: 10.2337/dbi15-0034Полозова Т.М., Шаповалов Д.Л. Когнитивные нарушения при сахарном диабете второго типа // Современная терапия психических расстройств. – 2015. – №2. – С.11-18. [Polozova TM, Shapovalov DL. Cognitive impairment in diabetes mellitus type 2. Sovremennaya terapiya psikhicheskikh rasstroistv. 2015;(2):11-18 (in Russ.)]Полозова Т.М., Шаповалов Д.Л. Когнитивные нарушения при сахарном диабете второго типа // Современная терапия психических расстройств. – 2015. – №2. – С.11-18. [Polozova TM, Shapovalov DL. Cognitive impairment in diabetes mellitus type 2. Sovremennaya terapiya psikhicheskikh rasstroistv. 2015;(2):11-18 (in Russ.)]Ryan CM, Williams TM. Effects of insulin-dependent diabetes on learning and memory efficiency in adults. J Clin Exp Neuropsychol. 1993;15(5):685-700. doi: 10.1080/01688639308402589Ryan CM, Williams TM. Effects of insulin-dependent diabetes on learning and memory efficiency in adults. J Clin Exp Neuropsychol. 1993;15(5):685-700. doi: 10.1080/01688639308402589Münch G, Cunningham AM, Riederer P, Braak E. Advanced glycation endproducts are associated with Hirano bodies in Alzheimer's disease. Brain Research. 1998;796(1-2):307-310. doi: 10.1016/s0006-8993(98)00328-xMünch G, Cunningham AM, Riederer P, Braak E. Advanced glycation endproducts are associated with Hirano bodies in Alzheimer's disease. Brain Research. 1998;796(1-2):307-310. doi: 10.1016/s0006-8993(98)00328-xde la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes—evidence reviewed. Journal of diabetes science and technology. 2008;2(6):1101-1113.de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes—evidence reviewed. Journal of diabetes science and technology. 2008;2(6):1101-1113.Ouwens DM, van Duinkerken E, Schoonenboom SN, et al. Cerebrospinal fluid levels of Alzheimer's disease biomarkers in middle-aged patients with type 1 diabetes. Diabetologia. 2014;57(10):2208-2214. doi: 10.1007/s00125-014-3333-6Ouwens DM, van Duinkerken E, Schoonenboom SN, et al. Cerebrospinal fluid levels of Alzheimer's disease biomarkers in middle-aged patients with type 1 diabetes. Diabetologia. 2014;57(10):2208-2214. doi: 10.1007/s00125-014-3333-6Biessels GJ, Staekenborg S, Brunner E, et al. Risk of dementia in diabetes mellitus: a systematic review. The Lancet Neurology. 2006;5(1):64-74. doi: 10.1016/s1474-4422(05)70284-2Biessels GJ, Staekenborg S, Brunner E, et al. Risk of dementia in diabetes mellitus: a systematic review. The Lancet Neurology. 2006;5(1):64-74. doi: 10.1016/s1474-4422(05)70284-2Unger JW, Moss AM, Livingston JN. Immunohistochemical localization of insulin receptors and phosphotyrosine in the brainstem of the adult rat. Neuroscience. 1991;42(3):853-861. doi: 10.1016/0306-4522(91)90049-tUnger JW, Moss AM, Livingston JN. Immunohistochemical localization of insulin receptors and phosphotyrosine in the brainstem of the adult rat. Neuroscience. 1991;42(3):853-861. doi: 10.1016/0306-4522(91)90049-tE. González-Reyes R, Aliev G, Avila-Rodrigues M, E. Barreto G. Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia. Current Pharmaceutical Design. 2016;22(7):812-818. doi: 10.2174/1381612822666151209152013E. González-Reyes R, Aliev G, Avila-Rodrigues M, E. Barreto G. Alterations in Glucose Metabolism on Cognition: A Possible Link Between Diabetes and Dementia. Current Pharmaceutical Design. 2016;22(7):812-818. doi: 10.2174/1381612822666151209152013Abbondante S, Baglietto-Vargas D, Rodriguez-Ortiz CJ, et al. Genetic ablation of tau mitigates cognitive impairment induced by type 1 diabetes. Am J Pathol. 2014;184(3):819-826. doi: 10.1016/j.ajpath.2013.11.021Abbondante S, Baglietto-Vargas D, Rodriguez-Ortiz CJ, et al. Genetic ablation of tau mitigates cognitive impairment induced by type 1 diabetes. Am J Pathol. 2014;184(3):819-826. doi: 10.1016/j.ajpath.2013.11.021Lu FP, Lin KP, Kuo HK. Diabetes and the risk of multi-system aging phenotypes: a systematic review and meta-analysis. PLoS One. 2009;4(1):e4144. doi: 10.1371/journal.pone.0004144Lu FP, Lin KP, Kuo HK. Diabetes and the risk of multi-system aging phenotypes: a systematic review and meta-analysis. PLoS One. 2009;4(1):e4144. doi: 10.1371/journal.pone.0004144Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004;29(2):95-102. doi: 10.1016/j.tibs.2003.12.004Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci. 2004;29(2):95-102. doi: 10.1016/j.tibs.2003.12.004Jolivalt CG, Lee CA, Beiswenger KK, et al. Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer's disease and correction by insulin. J Neurosci Res. 2008;86(15):3265-3274. doi: 10.1002/jnr.21787Jolivalt CG, Lee CA, Beiswenger KK, et al. Defective insulin signaling pathway and increased glycogen synthase kinase-3 activity in the brain of diabetic mice: parallels with Alzheimer's disease and correction by insulin. J Neurosci Res. 2008;86(15):3265-3274. doi: 10.1002/jnr.21787Desrocher M, Rovet J. Neurocognitive Correlates of Type 1 Diabetes Mellitus in Childhood. Child Neuropsychol. 2004;10(1):36-52. doi: 10.1076/chin.10.1.36.26241Desrocher M, Rovet J. Neurocognitive Correlates of Type 1 Diabetes Mellitus in Childhood. Child Neuropsychol. 2004;10(1):36-52. doi: 10.1076/chin.10.1.36.26241Manschot SM, Brands AMA, van der Grond J, et al. Brain Magnetic Resonance Imaging Correlates of Impaired Cognition in Patients With Type 2 Diabetes. Diabetes. 2006;55(4):1106-1113. doi: 10.2337/diabetes.55.04.06.db05-1323Manschot SM, Brands AMA, van der Grond J, et al. Brain Magnetic Resonance Imaging Correlates of Impaired Cognition in Patients With Type 2 Diabetes. Diabetes. 2006;55(4):1106-1113. doi: 10.2337/diabetes.55.04.06.db05-1323Qu Z, Jiao Z, Sun X, et al. Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain. Brain Res. 2011;1383:300-306. doi: 10.1016/j.brainres.2011.01.084Qu Z, Jiao Z, Sun X, et al. Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain. Brain Res. 2011;1383:300-306. doi: 10.1016/j.brainres.2011.01.084Hoffman WH, Artlett CM, Zhang W, et al. Receptor for advanced glycation end products and neuronal deficit in the fatal brain edema of diabetic ketoacidosis. Brain Res. 2008;1238:154-162. doi: 10.1016/j.brainres.2008.08.041Hoffman WH, Artlett CM, Zhang W, et al. Receptor for advanced glycation end products and neuronal deficit in the fatal brain edema of diabetic ketoacidosis. Brain Res. 2008;1238:154-162. doi: 10.1016/j.brainres.2008.08.041Jolivalt CG, Hurford R, Lee CA, et al. Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice. Exp Neurol. 2010;223(2):422-431. doi: 10.1016/j.expneurol.2009.11.005Jolivalt CG, Hurford R, Lee CA, et al. Type 1 diabetes exaggerates features of Alzheimer's disease in APP transgenic mice. Exp Neurol. 2010;223(2):422-431. doi: 10.1016/j.expneurol.2009.11.005Li J, Deng J, Sheng W, Zuo Z. Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol Biochem Behav. 2012;101(4):564-574. doi: 10.1016/j.pbb.2012.03.002Li J, Deng J, Sheng W, Zuo Z. Metformin attenuates Alzheimer's disease-like neuropathology in obese, leptin-resistant mice. Pharmacol Biochem Behav. 2012;101(4):564-574. doi: 10.1016/j.pbb.2012.03.002Jung HJ, Kim YJ, Eggert S, et al. Age-dependent increases in tau phosphorylation in the brains of type 2 diabetic rats correlate with a reduced expression of p62. Exp Neurol. 2013;248:441-450. doi: 10.1016/j.expneurol.2013.07.013Jung HJ, Kim YJ, Eggert S, et al. Age-dependent increases in tau phosphorylation in the brains of type 2 diabetic rats correlate with a reduced expression of p62. Exp Neurol. 2013;248:441-450. doi: 10.1016/j.expneurol.2013.07.013Kahn CR, White MF, Shoelson SE, et al. The Insulin Receptor and Its Substrate: Molecular Determinants of Early Events in Insulin Action. Recent ProgHorm Res 1993:291-339. doi: 10.1016/b978-0-12-571148-7.50015-4Kahn CR, White MF, Shoelson SE, et al. The Insulin Receptor and Its Substrate: Molecular Determinants of Early Events in Insulin Action. Recent ProgHorm Res 1993:291-339. doi: 10.1016/b978-0-12-571148-7.50015-4Rdzak GM, Abdelghany O. Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer's disease? Pharmacotherapy. 2014;34(12):1317-1323. doi: 10.1002/phar.1494Rdzak GM, Abdelghany O. Does insulin therapy for type 1 diabetes mellitus protect against Alzheimer's disease? Pharmacotherapy. 2014;34(12):1317-1323. doi: 10.1002/phar.1494Morales-Corraliza J, Wong H, Mazzella MJ, et al. Brain-Wide Insulin Resistance, Tau Phosphorylation Changes, and Hippocampal Neprilysin and Amyloid-beta Alterations in a Monkey Model of Type 1 Diabetes. J Neurosci. 2016;36(15):4248-4258. doi: 10.1523/JNEUROSCI.4640-14.2016Morales-Corraliza J, Wong H, Mazzella MJ, et al. Brain-Wide Insulin Resistance, Tau Phosphorylation Changes, and Hippocampal Neprilysin and Amyloid-beta Alterations in a Monkey Model of Type 1 Diabetes. J Neurosci. 2016;36(15):4248-4258. doi: 10.1523/JNEUROSCI.4640-14.2016Sajan M, Hansen B, Ivey R, 3rd, et al. Brain Insulin Signaling Is Increased in Insulin-Resistant States and Decreases in FOXOs and PGC-1alpha and Increases in Abeta1-40/42 and Phospho-Tau May Abet Alzheimer Development. Diabetes. 2016;65(7):1892-1903. doi: 10.2337/db15-1428Sajan M, Hansen B, Ivey R, 3rd, et al. Brain Insulin Signaling Is Increased in Insulin-Resistant States and Decreases in FOXOs and PGC-1alpha and Increases in Abeta1-40/42 and Phospho-Tau May Abet Alzheimer Development. Diabetes. 2016;65(7):1892-1903. doi: 10.2337/db15-1428Planel E, Tatebayashi Y, Miyasaka T, et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci. 2007;27(50):13635-13648. doi: 10.1523/JNEUROSCI.3949-07.2007Planel E, Tatebayashi Y, Miyasaka T, et al. Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci. 2007;27(50):13635-13648. doi: 10.1523/JNEUROSCI.3949-07.2007Clodfelder-Miller BJ, Zmijewska AA, Johnson GV, Jope RS. Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency. Diabetes. 2006;55(12):3320-3325. doi: 10.2337/db06-0485Clodfelder-Miller BJ, Zmijewska AA, Johnson GV, Jope RS. Tau is hyperphosphorylated at multiple sites in mouse brain in vivo after streptozotocin-induced insulin deficiency. Diabetes. 2006;55(12):3320-3325. doi: 10.2337/db06-0485Zhou Y, Zhao Y, Xie H, et al. Alteration in amyloid beta42, phosphorylated tau protein, interleukin 6, and acetylcholine during diabetes-accelerated memory dysfunction in diabetic rats: correlation of amyloid beta42 with changes in glucose metabolism. Behav Brain Funct. 2015;11:24. doi: 10.1186/s12993-015-0069-5Zhou Y, Zhao Y, Xie H, et al. Alteration in amyloid beta42, phosphorylated tau protein, interleukin 6, and acetylcholine during diabetes-accelerated memory dysfunction in diabetic rats: correlation of amyloid beta42 with changes in glucose metabolism. Behav Brain Funct. 2015;11:24. doi: 10.1186/s12993-015-0069-5Kim B, Backus C, Oh S, Feldman EL. Hyperglycemia-induced tau cleavage in vitro and in vivo: a possible link between diabetes and Alzheimer's disease. J Alzheimers Dis. 2013;34(3):727-739. doi: 10.3233/JAD-121669Kim B, Backus C, Oh S, Feldman EL. Hyperglycemia-induced tau cleavage in vitro and in vivo: a possible link between diabetes and Alzheimer's disease. J Alzheimers Dis. 2013;34(3):727-739. doi: 10.3233/JAD-121669Papon MA, El Khoury NB, Marcouiller F, et al. Deregulation of protein phosphatase 2A and hyperphosphorylation of tau protein following onset of diabetes in NOD mice. Diabetes. 2013;62(2):609-617. doi: 10.2337/db12-0187Papon MA, El Khoury NB, Marcouiller F, et al. Deregulation of protein phosphatase 2A and hyperphosphorylation of tau protein following onset of diabetes in NOD mice. Diabetes. 2013;62(2):609-617. doi: 10.2337/db12-0187Abbondante S, Baglietto-Vargas D, Rodriguez-Ortiz CJ, et al. Genetic ablation of tau mitigates cognitive impairment induced by type 1 diabetes. Am J Pathol. 2014;184(3):819-826. doi: 10.1016/j.ajpath.2013.11.021Abbondante S, Baglietto-Vargas D, Rodriguez-Ortiz CJ, et al. Genetic ablation of tau mitigates cognitive impairment induced by type 1 diabetes. Am J Pathol. 2014;184(3):819-826. doi: 10.1016/j.ajpath.2013.11.021Qu Z, Jiao Z, Sun X, et al. Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain. Brain Res. 2011;1383:300-306. doi: 10.1016/j.brainres.2011.01.084Qu Z, Jiao Z, Sun X, et al. Effects of streptozotocin-induced diabetes on tau phosphorylation in the rat brain. Brain Res. 2011;1383:300-306. doi: 10.1016/j.brainres.2011.01.084

The authors declare that there are no conflicts of interest present.