Extending Arms of Insulin Resistance from Diabetes to Alzheimer’s Disease: Identification of Potential Therapeutic Targets

Author(s): Smriti Gupta, Nitin Kumar Singhal, Subramaniam Ganesh, Rajat Sandhir*.

Journal Name: CNS & Neurological Disorders - Drug Targets

Volume 18 , Issue 3 , 2019

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Graphical Abstract:


Background & Objective: Type 3 diabetes (T3D) is chronic insulin resistant state of brain which shares pathology with sporadic Alzheimer’s disease (sAD). Insulin signaling is a highly conserved pathway in the living systems that orchestrate cell growth, repair, maintenance, energy homeostasis and reproduction. Although insulin is primarily studied as a key molecule in diabetes mellitus, its role has recently been implicated in the development of Alzheimer’s disease (AD). Severe complications in brain of diabetic patients and metabolically compromised status is evident in brain of AD patients. Underlying shared pathology of two disorders draws a trajectory from peripheral insulin resistance to insulin unresponsiveness in the central nervous system (CNS). As insulin has a pivotal role in AD, it is not an overreach to address diabetic condition in AD brain as T3D. Insulin signaling is indispensable to nervous system and it is vital for neuronal growth, repair, and maintenance of chemical milieu at synapses. Downstream mediators of insulin signaling pathway work as a regulatory hub for aggregation and clearance of unfolded proteins like Aβ and tau.

Conclusion: In this review, we discuss the regulatory roles of insulin as a pivotal molecule in brain with the understanding of defective insulin signaling as a key pathological mechanism in sAD. This article also highlights ongoing trials of targeting insulin signaling as a therapeutic manifestation to treat diabetic condition in brain.

Keywords: Alzheimer's disease, Amyloid beta, GSK3β, Insulin, Insulin degrading enzyme, miRNA, Type 3 Diabetes.

Pasquier F, Boulogne A, Leys D, Fontaine P. Diabetes mellitus and dementia. Diabetes Metab 2006; 32(5 Pt 1): 403-14.
Bekris LM, Yu CE, Bird TD, Tsuang DW. Genetics of Alzheimer Disease. J Geriatr Psychiatry Neurol 2010; 23(4): 213-27.
Virkamaki A, Ueki K, Kahn CR. Protein-protein interaction in insulin signaling and the molecular mechanisms of insulin resistance. J Clin Invest 1999; 103(7): 931-43.
Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease--is this type 3 diabetes? J Alzheimers Dis 2005; 7(1): 63-80.
Iwangoff P, Armbruster R, Enz A, Meier-Ruge W. Glycolytic enzymes from human autoptic brain cortex: Normal aged and demented cases. Mech Ageing Dev 1980; 14(1-2): 203-9.
de la Monte SM, Wands JR. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: Relevance to Alzheimer’s disease. J Alzheimers Dis 2005; 7(1): 45-61.
Sims-Robinson C, Kim B, Rosko A, Feldman EL. How does diabetes accelerate Alzheimer disease pathology? Nat Rev Neurol 2009; 6(10): 551-9.
Sandhir R, Gupta S. Molecular and biochemical trajectories from diabetes to Alzheimer’s disease: A critical appraisal. World J Diabetes 2015; 6(12): 1223-42.
Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes mellitus: A systematic review. Lancet Neurol 2006; 5(1): 64-74.
Zheng WH, Bastianetto S, Mennicken F, Ma W, Kar S. Amyloid beta peptide induces tau phosphorylation and loss of cholinergic neurons in rat primary septal cultures. Neuroscience 2002; 115(1): 201-11.
Butterfield DA, Di Domenico F, Barone E. Elevated risk of type 2 diabetes for development of Alzheimer disease: A key role for oxidative stress in brain. Biochim Biophys Acta 2007; 1842(9): 1693-706.
Doble BW, Woodgett JR. GSK-3: tricks of the trade for a multi-tasking kinase. J Cell Sci 2003; 116(Pt 7): 1175-86.
Havrankova J, Roth J, Brownstein M. Insulin receptors are widely distributed in the central nervous system of the rat. Nature 1978; 272(5656): 827-9.
Havrankova J, Schmechel D, Roth J, Brownstein M. Identification of insulin in rat brain. Proc Natl Acad Sci USA 1978; 75(11): 5737-41.
Gispen WH, Biessels GJ. Cognition and synaptic plasticity in diabetes mellitus. Trends Neurosci 2000; 23(11): 542-9.
Hoyer S. Glucose metabolism and insulin receptor signal transduction in Alzheimer disease. Eur J Pharmacol 2004; 490(1-3): 115-25.
Frölich L, Blum DD, Bernstein HG, et al. Brain insulin and insulin receptors in aging and sporadic Alzheimer’s disease. J Neural Trans 1998; 105(4-5): 423-38.
Li L, Holscher C. Common pathological processes in Alzheimer disease and type 2 diabetes: A review. Brain Res Rev 2007; 56(2): 384-402.
Kompoti M, Mariolis A, Alevizos A, et al. Elevated serum triglycerides is the strongest single indicator for the presence of metabolic syndrome in patients with type 2 diabetes. Cardiovasc Diabetol 2006; 5: 21.
Brito GN. 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; 1(1): 7.
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; 71(3): 365-76.
Schulingkamp RJ, Pagano TC, Hung D, Raffa RB. Insulin receptors and insulin action in the brain: Review and clinical implications. Neurosci Biobehav Rev 2000; 24(8): 855-72.
Benedict C, Hallschmid M, Schmitz K, Schultes B, Ratter F, Fehm HL. Intranasal insulin improves memory in humans: Superiority of insulin aspart. Neuropsychopharmacology 2007; 32(1): 239-43.
Zhao W, Chen H, Xu H, Moore E, Meiri N, Quon MJ. Brain insulin receptors and spatial memory. Correlated changes in gene expression, tyrosine phosphorylation, and signaling molecules in the hippocampus of water maze trained rats. J Biol Chem 1999; 274(49): 34893-902.
Blazquez E, Velazquez E, Hurtado-Carneiro V, Ruiz-Albusac JM. Insulin in the brain: Its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol 2004; 5: 161.
Ghasemi R, Haeri A, Dargahi L, Mohamed Z, Ahmadiani A. Insulin in the brain: Sources, localization and functions. Mol Neurobiol 2013; 47(1): 145-71.
Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest 2009; 122(4): 1316-38.
Faiq MA, Dada T. Diabetes Type 4: a paradigm shifts in the understanding of glaucoma, the brain specific diabetes and the candidature of insulin as a therapeutic agent. Curr Mol Med 2017; 17(1): 46-59.
Lancour D, Naj A, Mayeux R, et al. One for all and all for one: improving replication of genetic studies through network diffusion. PLoS Genet 2018; 14(4): e1007306.
Cook DG, Leverenz JB, McMillan PJ, Kulstad JJ, Ericksen S, Roth RA. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer’s disease is associated with the apolipoprotein E-epsilon4 allele. Am J Pathol 2003; 162(1): 313-9.
Perez A, Morelli L, Cresto JC, Castano EM. Degradation of soluble amyloid beta-peptides 1-40, 1-42, and the Dutch variant 1-40Q by insulin degrading enzyme from Alzheimer disease and control brains. Neurochem Res 2000; 25(2): 247-55.
Mittal K, Mani RJ, Katare DP. Type 3 diabetes: Cross talk between differentially regulated proteins of type 2 diabetes mellitus and Alzheimer’s Disease. Sci Rep 2012; 6: 25589.
de la Monte SM, Wands JR. Alzheimer’s disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol 2008; 2(6): 1101-13.
de la Monte SM, Tong M. Mechanisms of nitrosamine-mediated neurodegeneration: Potential relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 2009; 17(4): 817-25.
Werner H, LeRoith D. Insulin and insulin-like growth factor receptors in the brain: Physiological and pathological aspects. Eur Neuropsychopharmacol 2007; 24(12): 1947-53.
Banks WA, Owen JW, Erickson MA. Insulin in the brain: There and back again. Pharmacol Ther 2012; 136(1): 82-93.
Rivera EJ, Goldin A, Fulmer N, Tavares R, Wands JR, de la Monte SM. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer’s disease: Link to brain reductions in acetylcholine. J Alzheimers Dis 2005; 8(3): 247-68.
Lester-Coll N, Rivera EJ, Soscia SJ, Doiron K, Wands JR, de la Monte SM. Intracerebral streptozotocin model of type 3 diabetes: Relevance to sporadic Alzheimer’s disease. J Alzheimers Dis 2006; 9(1): 13-33.
Soscia SJ, Tong M, Xu XJ, et al. Chronic gestational exposure to ethanol causes insulin and IGF resistance and impairs acetylcholine homeostasis in the brain. Cell Mol Life Sci 2006; 63(17): 2039-56.
Wei LT, Matsumoto H, Rhoads DE. Release of immunoreactive insulin from rat brain synaptosomes under depolarizing conditions. J Neurochem 1990; 54(5): 1661-5.
Zhao WQ, Chen H, Quon MJ, Alkon DL. Insulin and the insulin receptor in experimental models of learning and memory. Eur J Pharmacol 2004; 490(1-3): 71-81.
Abraham MA, Filippi BM, Kang GM, Kim MS, Lam TK. Insulin action in the hypothalamus and dorsal vagal complex. Exp Physiol 2014; 99(9): 1104-9.
Lee SH, Zabolotny JM, Huang H, Lee H, Kim YB. Insulin in the nervous system and the mind: Functions in metabolism, memory, and mood. Mol Metab 2016; 5(8): 589-601.
Duarte AI, Santos P, Oliveira CR, Santos MS, Rego AC. Insulin neuroprotection against oxidative stress is mediated by Akt and GSK-3beta signaling pathways and changes in protein expression. Biochim Biophys Acta 2008; 1783(6): 994-1002.
Stouffer MA, Woods CA, Patel JC, et al. Insulin enhances striatal dopamine release by activating cholinergic interneurons and thereby signals reward. Nat Commun 2015; 6: 8543.
de la Monte SM, Wands JR. Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease. J Alzheimers Dis 2006; 9(2): 167-81.
Holscher C. Nitric oxide, the enigmatic neuronal messenger: Its role in synaptic plasticity. Trends Neurosci 1997; 20(7): 298-303.
Lin JW, Ju W, Foster K, Lee SH, Ahmadian G, Wyszynski M. Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization. Nat Neurosci 2000; 3(12): 1282-90.
Eldar-Finkelman H, Schreyer SA, Shinohara MM, LeBoeuf RC, Krebs EG. Increased glycogen synthase kinase-3 activity in diabetes- and obesity-prone C57BL/6J mice. Diabetes 1999; 48(8): 1662-6.
Geroldi C, Frisoni GB, Paolisso G, Bandinelli S, Lamponi M, Abbatecola AM. Insulin resistance in cognitive impairment: The InCHIANTI study. Arch Neurol 2005; 62(7): 1067-72.
Gupta S, Yadav K, Mantri SS, Singhal NK, Ganesh S, Sandhir R. Evidence for compromised insulin signaling and neuronal vulnerability in experimental model of sporadic Alzheimer’s Disease. Mol Neurobiol 2018. [Epub ahead of print].
Schubert M, Gautam D, Surjo D, Ueki K, Baudler S, Schubert D. Role for neuronal insulin resistance in neurodegenerative diseases. Proc Natl Acad Sci USA 2004; 101(9): 3100-5.
Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA. Pancreatic extracts in the treatment of diabetes mellitus. Can Med Assoc J 1922; 12(3): 141-6.
Kopf SR, Baratti CM. Effects of post training administration of insulin on retention of a habituation response in mice: Participation of a central cholinergic mechanism. Neurobiol Learn Mem 1999; 71(1): 50-61.
Huang CC, You JL, Lee CC, Hsu KS. Insulin induces a novel form of postsynaptic mossy fiber long-term depression in the hippocampus. Mol Cell Neurosci 2003; 24(3): 831-41.
Watson GS, Craft S. The role of insulin resistance in the pathogenesis of Alzheimer’s disease: Implications for treatment. CNS Drugs 2003; 17(1): 27-45.
Freiherr J, Hallschmid M, Frey WH, Brunner YF, Chapman CD, Holscher C. Intranasal insulin as a treatment for Alzheimer’s disease: A review of basic research and clinical evidence. CNS Drugs 2009; 27(7): 505-14.
Medova M, Aebersold DM, Zimmer Y. The molecular crosstalk between the met receptor tyrosine kinase and the dna damage response-biological and clinical aspects. Cancers (Basel) 2009; 6(1): 1-27.
Moosavi M, Naghdi N, Maghsoudi N, Zahedi Asl S. The effect of intrahippocampal insulin microinjection on spatial learning and memory. Horm Behav 2006; 50(5): 748-52.
Wang YT, Salter MW. Regulation of NMDA receptors by tyrosine kinases and phosphatases. Nature 1994; 369(6477): 233-5.
Blanchard JG, Duncan PM. Effect of combinations of insulin, glucose and scopolamine on radial arm maze performance. Pharmacol Biochem Behav 1997; 58(1): 209-14.
van der Heide LP, Kamal A, Artola A, Gispen WH, Ramakers GM. Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner. J Neurochem 2005; 94(4): 1158-66.
Gasparini L, Xu H. Potential roles of insulin and IGF-1 in Alzheimer’s disease. Trends Neurosci 2003; 26(8): 404-6.
Kurochkin IV. Insulin-degrading enzyme: Embarking on amyloid destruction. Trends Biochem Sci 2001; 26(7): 421-5.
Schrijvers EM, Witteman JC, Sijbrands EJ, Hofman A, Koudstaal PJ, Breteler MM. Insulin metabolism and the risk of Alzheimer disease: The Rotterdam Study. Neurology 2007; 75(22): 1982-7.
Bingham EM, Hopkins D, Smith D, Pernet A, Hallett W, Reed L. The role of insulin in human brain glucose metabolism: An 18fluoro-deoxyglucose positron emission tomography study. Diabetes 2002; 51(12): 3384-90.
Segel SA, Fanelli CG, Dence CS, Markham J, Videen TO, Paramore DS. Blood-to-brain glucose transport, cerebral glucose metabolism, and cerebral blood flow are not increased after hypoglycemia. Diabetes 2001; 50(8): 1911-7.
El Messari S, Leloup C, Quignon M, Brisorgueil MJ, Penicaud L, Arluison M. Immunocytochemical localization of the insulin-responsive glucose transporter 4 (Glut4) in the rat central nervous system. J Comp Neurol 1998; 399(4): 492-512.
Ibberson M, Uldry M, Thorens B. GLUTX1, a novel mammalian glucose transporter expressed in the central nervous system and insulin-sensitive tissues. J Biol Chem 2000; 275(7): 4607-12.
Figlewicz DP, Szot P, Israel PA, Payne C, Dorsa DM. Insulin reduces norepinephrine transporter mRNA in vivo in rat locus coeruleus. Brain Res 1993; 602(1): 161-4.
Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY. Recruitment of functional GABA(A) receptors to postsynaptic domains by insulin. Nature 1997; 388(6643): 686-90.
Man HY, Lin JW, Ju WH, Ahmadian G, Liu L, Becker LE. Regulation of AMPA receptor-mediated synaptic transmission by clathrin-dependent receptor internalization. Neuron 2000; 25(3): 649-62.
Luo D, Hou X, Hou L, Wang M, Xu S, Dong C. Effect of pioglitazone on altered expression of Abeta metabolism-associated molecules in the brain of fructose-drinking rats, a rodent model of insulin resistance. Eur J Pharmacol 2016; 664(1-3): 14-9.
Solano DC, Sironi M, Bonfini C, Solerte SB, Govoni S, Racchi M. Insulin regulates soluble amyloid precursor protein release via phosphatidyl inositol 3 kinase-dependent pathway. FASEB J 2000; 14(7): 1015-22.
Gasparini L, Gouras GK, Wang R, Gross RS, Beal MF, Greengard P. Stimulation of beta-amyloid precursor protein trafficking by insulin reduces intraneuronal beta-amyloid and requires mitogen-activated protein kinase signaling. J Neurosci 2001; 21(8): 2561-70.
Furukawa K, Sopher BL, Rydel RE, et al. Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem 1996; 67(5): 1882-96.
Ashpole NM, Sanders JE, Hodges EL, Yan H, Sonntag WE. Growth hormone, insulin-like growth factor-1 and the aging brain. Exp Gerontol 2017; 68: 76-81.
Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I. Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med 2002; 8(12): 1390-7.
Qiu WQ, Walsh DM, Ye Z, Vekrellis K, Zhang J, Podlisny MB. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. J Biol Chem 1998; 273(49): 32730-8.
Sudoh S, Frosch MP, Wolf BA. Differential effects of proteases involved in intracellular degradation of amyloid beta-protein between detergent-soluble and -insoluble pools in CHO-695 cells. Biochemistry 2002; 41(4): 1091-9.
Zhao L, Teter B, Morihara T, Lim GP, Ambegaokar SS, Ubeda OJ. Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: Implications for Alzheimer’s disease intervention. J Neurosci 2004; 24(49): 11120-6.
Farris W, Mansourian S, Chang Y, Lindsley L, Eckman EA, Frosch MP. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Proc Natl Acad Sci USA 2003; 100(7): 4162-7.
Leissring MA, Farris W, Chang AY, Walsh DM, Wu X, Sun X. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 2003; 40(6): 1087-93.
Zhao WQ, Lacor PN, Chen H, Lambert MP, Quon MJ, Krafft GA. Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric abeta. J Biol Chem 2009; 284(28): 18742-53.
Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ. Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J 2008; 22(1): 246-60.
Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE. Al zheimer’s disease-affected brain: Presence of oligomeric A beta ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA 2003; 100(18): 10417-22.
Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL. Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 2007; 27(11): 2866-75.
Calkins MJ, Manczak M, Mao P, Shirendeb U, Reddy PH. Impaired mitochondrial biogenesis, defective axonal transport of mitochondria, abnormal mitochondrial dynamics and synaptic degeneration in a mouse model of Alzheimer’s disease. Hum Mol Genet 2007; 20(23): 4515-29.
Townsend M, Mehta T, Selkoe DJ. Soluble Abeta inhibits specific signal transduction cascades common to the insulin receptor pathway. J Biol Chem 2007; 282(46): 33305-12.
De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP. Protection of synapses against Alzheimer’s-linked toxins: Insulin signaling prevents the pathogenic binding of Abeta oligomers. Proc Natl Acad Sci USA 2009; 106(6): 1971-6.
Liu X, Teng Z, Cui C, Wang R, Liu M, Zhang Y. Amyloid beta-derived diffusible ligands (ADDLs) induce abnormal expression of insulin receptors in rat hippocampal neurons. J Mol Neurosci 2006; 52(1): 124-30.
Ma QL, Yang F, Rosario ER, Ubeda OJ, Beech W, Gant DJ. Beta-amyloid oligomers induce phosphorylation of tau and inactivation of insulin receptor substrate via c-Jun N-terminal kinase signaling: Suppression by omega-3 fatty acids and curcumin. J Neurosci 2009; 29(28): 9078-89.
Grundke-Iqbal I, Iqbal K, Tung YC, Quinlan M, Wisniewski HM, Binder LI. Abnormal phosphorylation of the microtubule-associated protein tau (tau) in Alzheimer cytoskeletal pathology. Proc Natl Acad Sci USA 1986; 83(13): 4913-7.
Vidal R, Calero M, Piccardo P, Farlow MR, Unverzagt FW, Mendez E. Senile dementia associated with amyloid beta protein angiopathy and tau perivascular pathology but not neuritic plaques in patients homozygous for the APOE-epsilon4 allele. Acta Neuropathol 2000; 100(1): 1-12.
Oddo S. The ubiquitin-proteasome system in Alzheimer’s disease. J Cell Mol Med 2008; 12(2): 363-73.
Bhat R, Xue Y, Berg S, Hellberg S, Ormo M, Nilsson Y. Structural insights and biological effects of glycogen synthase kinase 3-specific inhibitor AR-A014418. J Biol Chem 2003; 278(46): 45937-45.
Maj M, Hoermann G, Rasul S, Base W, Wagner L, Attems J. The microtubule-associated protein tau and its relevance for pancreatic beta cells. J Diabetes Res 2016; 17: 1964634.
Morales I, Farias G, Maccioni RB. Neuroimmunomodulation in the pathogenesis of Alzheimer’s disease. Neuroimmunomodulation 2008; 17(3): 202-4.
de la Monte SM. Contributions of brain insulin resistance and deficiency in amyloid-related neurodegeneration in Alzheimer’s disease. Drugs 2012; 72(1): 49-66.
Henderson ST. High carbohydrate diets and Alzheimer’s disease. Med Hypotheses 2004; 62(5): 689-700.
Reiman EM, Chen K, Alexander GE, Caselli RJ, Bandy D, Osborne D. Functional brain abnormalities in young adults at genetic risk for late-onset Alzheimer’s dementia. Proc Natl Acad Sci USA 2004; 101(1): 284-9.
Reiman EM, Caselli RJ, Yun LS, Chen K, Bandy D, Minoshima S. Preclinical evidence of Alzheimer’s disease in persons homozygous for the epsilon 4 allele for apolipoprotein E. N Engl J Med 1996; 334(12): 752-8.
Fukuyama H, Ogawa M, Yamauchi H, Yamaguchi S, Kimura J, Yonekura Y. Altered cerebral energy metabolism in Alzheimer’s disease: A PET study. J Nucl Med 1994; 35(1): 1-6.
Correia SC, Santos RX, Carvalho C, Cardoso S, Candeias E, Santos MS. Insulin signaling, glucose metabolism and mitochondria: Major players in Alzheimer’s disease and diabetes interrelation. Brain Res 2011; 1441: 64-78.
Mosconi L, De Santi S, Li J, Tsui WH, Li Y, Boppana M. Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol Aging 2008; 29(5): 676-92.
Kandimalla R, Thirumala V, Reddy PH. Is Alzheimer’s disease a Type 3 Diabetes? A critical appraisal. Biochim Biophys Acta 2008; 1863(5): 1078-89.
Mamelak M. Alzheimer’ s disease, oxidative stress and gammahydroxybutyrate. Neurobiol Aging 2007; 28(9): 1340-60.
Minoshima S, Giordani B, Berent S, Frey KA, Foster NL, Kuhl DE. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer’s disease. Ann Neurol 1997; 42(1): 85-94.
Mosconi L. Brain glucose metabolism in the early and specific diagnosis of Alzheimer’s disease. FDG-PET studies in MCI and AD. Eur J Nucl Med Mol Imaging 2005; 32(4): 486-510.
Pappata S, Salvatore E, Postiglione A. In vivo imaging of neurotransmission and brain receptors in dementia. J Neuroimaging 2008; 18(2): 111-24.
Tateno M, Kobayashi S, Saito T. Imaging improves diagnosis of dementia with lewy bodies. Psychiatry Investig 2009; 6(4): 233-40.
Simpson IA, Chundu KR, Davies-Hill T, Honer WG, Davies P. Decreased concentrations of GLUT1 and GLUT3 glucose transporters in the brains of patients with Alzheimer’s disease. Ann Neurol 1994; 35(5): 546-51.
Harr SD, Simonian NA, Hyman BT. Functional alterations in Alzheimer’s disease: Decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. J Neuropathol Exp Neurol 1995; 54(1): 38-41.
Mooradian AD, Chung HC, Shah GN. GLUT-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol Aging 1997; 18(5): 469-74.
Liu Y, Liu F, Iqbal K, Grundke-Iqbal I, Gong CX. Decreased glucose transporters correlate to abnormal hyperphosphorylation of tau in Alzheimer disease. FEBS Lett 2008; 582(2): 359-64.
Liu F, Shi J, Tanimukai H, Gu J, Grundke-Iqbal I, Iqbal K. Reduced O-GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain 2009; 132(Pt 7): 1820-32.
Beal MF. Mitochondria take centre stage in aging and neurodegeneration. Ann Neurol 2005; 58(4): 495-505.
Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE. Mitochondrial abnormalities in Alzheimer brain: Mechanistic implications. Ann Neurol 2005; 57(5): 695-703.
Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Science 2004; 304(5669): 448-52.
Gibson GE, Sheu KF, Blass JP, Baker A, Carlson KC, Harding B. Reduced activities of thiamine-dependent enzymes in the brains and peripheral tissues of patients with Alzheimer’s disease. Arch Neurol 1988; 45(8): 836-40.
Sheu KF, Clarke DD, Kim YT, Blass JP, Harding BJ, DeCicco J. Studies of transketolase abnormality in Alzheimer’s disease. Arch Neurol 1988; 45(8): 841-5.
Sorbi S, Bird ED, Blass JP. Decreased pyruvate dehydrogenase complex activity in Huntington and Alzheimer brain. Ann Neurol 1983; 13(1): 72-8.
Mastrogiacoma F, Bettendorff L, Grisar T, Kish SJ. Brain thiamine, its phosphate esters, and its metabolizing enzymes in Alzheimer’s disease. Ann Neurol 1996; 39(5): 585-91.
Gold M, Hauser RA, Chen MF. Plasma thiamine deficiency associated with Alzheimer’s disease but not Parkinson’s disease. Metab Brain Dis 1998; 13(1): 43-53.
Butterworth RF, Kril JJ, Harper CG. Thiamine-dependent enzyme changes in the brains of alcoholics: Relationship to the Wernicke-Korsakoff syndrome. Alcohol Clin Exp Res 1993; 17(5): 1084-8.
Shoffner JM. Oxidative phosphorylation defects and Alzheimer’s disease. Neurogenetics 1997; 1(1): 13-9.
Szkudelski T. The mechanism of alloxan and streptozotocin action in B cells of the rat pancreas. Physiol Res 2001; 50(6): 537-46.
Paweł G. Intracerebroventricular streptozotocin injections as a model of alzheimer’s disease: In search of a relevant mechanism. Mol Neurobiol 2016; 53(3): 1741-52.
Plaschke K, Hoyer S. Action of the diabetogenic drug streptozotocin on glycolytic and glycogenolytic metabolism in adult rat brain cortex and hippocampus. Int J Dev Neurosci 1993; 11(4): 477-83.
Duelli R, Schrock H, Kuschinsky W, Hoyer S. Intracerebroventricular injection of streptozotocin induces discrete local changes in cerebral glucose utilization in rats. Int J Dev Neurosci 1994; 12(8): 737-43.
Hoyer S, Lee SK, Loffler T, Schliebs R. Inhibition of the neuronal insulin receptor. An in vivo model for sporadic Alzheimer disease? Ann N Y Acad Sci 2000; 920: 256-8.
Lannert H, Hoyer S. Intracerebroventricular administration of streptozotocin causes long-term diminutions in learning and memory abilities and in cerebral energy metabolism in adult rats. Behav Neurosci 1998; 112(5): 1199-208.
Benedict C, Hallschmid M, Hatke A, Schultes B, Fehm HL, Born J. Intranasal insulin improves memory in humans. Psychoneuroendocrinology 2004; 29(10): 1326-34.
McNay EC, Ong CT, McCrimmon RJ, Cresswell J, Bogan JS, Sherwin RS. Hippocampal memory processes are modulated by insulin and high-fat-induced insulin resistance. Neurobiol Learn Mem 2009; 93(4): 546-53.
Craft S, Baker LD, Montine TJ, Minoshima S, Watson GS, Claxton A. Intranasal insulin therapy for Alzheimer disease and amnestic mild cognitive impairment: A pilot clinical trial. Arch Neurol 2004; 69(1): 29-38.
Born J, Lange T, Kern W, McGregor GP, Bickel U, Fehm HL. Sniffing neuropeptides: A transnasal approach to the human brain. Nat Neurosci 2002; 5(6): 514-6.
Dhamoon MS, Noble JM, Craft S. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2009; 72(3): 292-3.
Djupesland PG. Intranasal insulin improves cognition and modulates beta-amyloid in early AD. Neurology 2008; 71(11): 864.
Morris JK, Burns JM. Insulin: An emerging treatment for Alzheimer’s disease dementia? Curr Neurol Neurosci Rep 2012; 12(5): 520-7.
Hanefeld M. Pioglitazone and sulfonylureas: Effectively treating type 2 diabetes. Int J Clin Pract Suppl 2007; 61(153): 20-7.
Choi JH, Banks AS, Estall JL, et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5. Nature 2010; 466(7305): 451-6.
Escribano L, Simón AM, Gimeno E, et al. Rosiglitazone rescues memory impairment in Alzheimer’s transgenic mice: Mechanisms involving a reduced amyloid and tau pathology. Neuropsychopharmacology 2010; 35(7): 1593-604.
Angela M, Abbatecola SJ, Lattanzio F, et al. Rosiglitazone and cognitive stability in older individuals with type 2 diabetes and mild cognitive impairment. Diabetes Care 2010; 33(8): 1706-11.
Kim SH, Abbasi F, Chu JW. Rosiglitazone reduces glucose-stimulated insulin secretion rate and increases insulin clearance in nondiabetic, insulin-resistant individuals. Diabetes 2005; 54(8): 2447-52.
Gupta A, Bisht B, Dey CS. Peripheral insulin-sensitizer drug metformin ameliorates neuronal insulin resistance and Alzheimer’s-like changes. Neuropharmacology 2011; 60(6): 910-20.
Lebovitz HE, Banerji MA. Insulin resistance and its treatment by thiazolidinediones. Recent Prog Horm Res 2001; 56: 265-94.
Weinstein SP, Holand A, O’Boyle E, Haber RS. Effects of thiazolidinediones on glucocorticoid-induced insulin resistance and GLUT4 glucose transporter expression in rat skeletal muscle. Metabolism 1993; 42(10): 1365-9.
Koenig AM, Mechanic-Hamilton D, Xie SX, Combs MF, Cappola AR, Xie L. Effects of the insulin sensitizer metformin in alzheimer disease: Pilot data from a randomized placebo-controlled crossover study. Alzheimer Dis Assoc Disord 1997; 31(2): 107-13.
Labuzek K, Suchy D, Gabryel B, Bielecka A, Liber S, Okopien B. Quantification of metformin by the HPLC method in brain regions, cerebrospinal fluid and plasma of rats treated with lipopolysaccharide. Pharmacol Rep 2008; 62(5): 956-65.
Nath N, Khan M, Paintlia MK, Singh I, Hoda MN, Giri S. Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J Immunol 2009; 182(12): 8005-14.
David D'Alessio. Is GLP-1 a hormone: Whether and When? J Diabetes Investig 2016; 7(Suppl Suppl 1): 50-55..
Perry TA, Greig NH. A new Alzheimer’s disease interventive strategy: GLP-1. Curr Drug Targets 2004; 5(6): 565-71.
McClean PL, Parthsarathy V, Faivre E, Holscher C. The diabetes drug liraglutide prevents degenerative processes in a mouse model of Alzheimer’s disease. J Neurosci 2010; 31(17): 6587-94.
Li XL, Aou S, Oomura Y, Hori N, Fukunaga K, Hori T. Impairment of long-term potentiation and spatial memory in leptin receptor-deficient rodents. Neuroscience 2002; 113(3): 607-15.
Chan JL, Lutz K, Cochran E, Huang W, Peters Y, Weyer C. Clinical effects of long-term metreleptin treatment in patients with lipodystrophy. Endocr Pract 2010; 17(6): 922-32.
Ravussin E, Smith SR, Mitchell JA, Shringarpure R, Shan K, Maier H. Enhanced weight loss with pramlintide/metreleptin: An integrated neurohormonal approach to obesity pharmacotherapy. Obesity 2009; 17(9): 1736-43.
Adler BL, Yarchoan M, Hwang HM, Louneva N, Blair JA, Palm R. Neuroprotective effects of the amylin analogue pramlintide on Alzheimer’s disease pathogenesis and cognition. Neurobiol Aging 2008; 35(4): 793-801.
Furman B, Ong WK, Pyne NJ. Cyclic AMP signaling in pancreatic islets. Adv Exp Med Biol 2006; 654: 281-304.
Song WJ, Seshadri M, Ashraf U, Mdluli T, Mondal P, Keil M. Snapin mediates incretin action and augments glucose-dependent insulin secretion. Cell Metab 2003; 13(3): 308-19.
Hamilton A, Holscher C. Receptors for the incretin glucagon-like peptide-1 are expressed on neurons in the central nervous system. Neuroreport 2009 Aug 26;; 20(13): 1161-6.
Ghosal S, Myers B, Herman JP. Role of central glucagon-like peptide-1 in stress regulation. Physiol Behav 2008; 122: 201-7.
Holscher C, Li L. New roles for insulin-like hormones in neuronal signalling and protection: New hopes for novel treatments of Alzheimer’s disease? Neurobiol Aging 2009; 31(9): 1495-502.
Edavalath M, Stephens JW. Liraglutide in the treatment of type 2 diabetes mellitus: Clinical utility and patient perspectives. Patient Prefer Adherence 2010; 4: 61-8.
Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels in type 2 diabetes. J Clin Endocrinol Metab 2004; 89(5): 2078-84.
Cantuti CL, Givogri MI, Hebert A, Smith B, Song Y, Kaminska A. The sphingolipid psychosine inhibits fast axonal transport in Krabbe disease by activation of GSK3beta and deregulation of molecular motors. J Neurosci 2012; 33(24): 10048-56.
Decker H, Lo KY, Unger SM, Ferreira ST, Silverman MA. Amyloid-beta peptide oligomers disrupt axonal transport through an NMDA receptor-dependent mechanism that is mediated by glycogen synthase kinase 3beta in primary cultured hippocampal neurons. J Neurosci 2007; 30(27): 9166-71.
DeFuria J, Shea TB. Arsenic inhibits neurofilament transport and induces perikaryal accumulation of phosphorylated neurofilaments: Roles of JNK and GSK-3beta. Brain Res 2007; 1181: 74-82.
Ramser EM, Gan KJ, Decker H, Fan EY, Suzuki MM, Ferreira ST. Amyloid-beta oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons. Mol Biol Cell 2007; 24(16): 2494-505.
Peineau S, Taghibiglou C, Bradley C, et al. LTP inhibits LTD in the hippocampus via regulation of GSK3beta. Neuron 2007; 53(5): 703-17.
Phiel CJ, Klein PS. Molecular targets of lithium action. Annu Rev Pharmacol Toxicol 2001; 41: 789-813.
De Sarno P, Li X, Jope RS. Regulation of Akt and glycogen synthase kinase-3 beta phosphorylation by sodium valproate and lithium. Neuropharmacology 2002; 43(7): 1158-64.
Qu ZS, Tian Q, Zhou XW, Wang Q, Zhang Q, Wang JZ. Mechanism of tau hyperphosphorylation in brain cortex of diabetic rats and effect of LiCl. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2006; 28(2): 244-8.
Ryder J, Su Y, Liu F, Li B, Zhou Y, Ni B. Divergent roles of GSK3 and CDK5 in APP processing. Biochem Biophys Res Commun 2003; 312(4): 922-9.
Phukan S, Babu VS, Kannoji A, Hariharan R, Balaji VN. GSK3beta: Role in therapeutic landscape and development of modulators. Br J Pharmacol 2007; 160(1): 1-19.
Leost M, Schultz C, Link A, Wu YZ, Biernat J, Mandelkow EM. Paullones are potent inhibitors of glycogen synthase kinase-3beta and cyclin-dependent kinase 5/p25. Eur J Biochem 2000; 267(19): 5983-94.
Leclerc S, Garnier M, Hoessel R, Marko D, Bibb JA, Snyder GL. Indirubins inhibit glycogen synthase kinase-3 beta and CDK5/p25, two protein kinases involved in abnormal tau phosphorylation in Alzheimer’s disease. A property common to most cyclin-dependent kinase inhibitors? J Biol Chem 2001; 276(1): 251-60.
Smith DG, Buffet M, Fenwick AE, Haigh D, Ife RJ, Saunders M. 3-Anilino-4-arylmaleimides: Potent and selective inhibitors of glycogen synthase kinase-3 (GSK-3). Bioorg Med Chem Lett 2001; 11(5): 635-9.
Martinez A, Alonso M, Castro A, Perez C, Moreno FJ. First non-ATP competitive glycogen synthase kinase 3 beta (GSK-3beta) inhibitors: Thiadiazolidinones (TDZD) as potential drugs for the treatment of Alzheimer’s disease. J Med Chem 2002; 45(6): 1292-9.
Gupta S, Verma S, Mantri S, Berman NE, Sandhir R. Targeting MicroRNAs in prevention and treatment of neurodegenerative disorders. Drug Dev Res 2015; 76(7): 397-418.
Tian T, Mingyi M, Qiu X, Qiu Y. MicroRNA-101 reverses temozolomide resistance by inhibition of GSK3beta in glioblastoma. Oncotarget 2009; 7(48): 79584-95.
Chen H, Wang S, Chen L, Chen Y, Wu M, Zhang Y. MicroRNA-344 inhibits 3T3-L1 cell differentiation via targeting GSK3beta of Wnt/beta-catenin signaling pathway. FEBS Lett 2011; 588(3): 429-35.
Bai X, Meng L, Sun H, Li Z, Zhang X, Hua S. MicroRNA-196b inhibits cell growth and metastasis of lung cancer cells by targeting runx2. Cell Physiol Biochem 2007; 43(2): 757-67.
Sun X, Lin J, Zhang Y, Kang S, Belkin N, Wara AK. MicroRNA-181b improves glucose homeostasis and insulin sensitivity by regulating endothelial function in white adipose tissue. Circ Res 2001; 118(5): 810-21.
Agarwal P, Srivastava R, Srivastava AK, Ali S, Datta M. miR-135a targets IRS2 and regulates insulin signaling and glucose uptake in the diabetic gastrocnemius skeletal muscle. Biochim Biophys Acta 2008; 1832(8): 1294-303.
Zhou T, Meng X, Che H, Shen N, Xiao D, Song X. Regulation of insulin resistance by multiple MiRNAs via targeting the GLUT4 signalling pathway. Cell Physiol Biochem 38(5): 2063-78.
Karolina DS, Armugam A, Tavintharan S, Wong MT, Lim SC, Sum CF. MicroRNA 144 impairs insulin signaling by inhibiting the expression of insulin receptor substrate 1 in type 2 diabetes mellitus. PLoS One 2011; 6(8): e22839.
Pivovarova O, Hohn A, Grune T, Pfeiffer AF, Rudovich N. Insulin-degrading enzyme: New therapeutic target for diabetes and Alzheimer’s disease? Ann Med 2015; 48(8): 614-24.

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Year: 2019
Page: [172 - 184]
Pages: 13
DOI: 10.2174/1871527317666181114163515
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