Abstract
Insulin deficiency or resistance can promote dementia and hallmarks of Alzheimer's disease (AD). The formation of neurofibrillary tangles of p-TAU protein, extracellular Aβ plaques, and neuronal loss is related to the switching off insulin signaling in cognition brain areas. Metformin is a biguanide antihyperglycemic drug used worldwide for the treatment of type 2 diabetes. Some studies have demonstrated that metformin exerts neuroprotective, anti-inflammatory, anti-oxidant, and nootropic effects. This study aimed to evaluate metformin's effects on long-term memory and p-Tau and amyloid β modulation, which are hallmarks of AD in diabetic mice. Swiss Webster mice were distributed in the following experimental groups: control; treated with streptozotocin (STZ) that is an agent toxic to the insulin-producing beta cells; STZ + metformin 200 mg/kg (M200). STZ mice showed significant augmentation of time spent to reach the target box in the Barnes maze, while M200 mice showed a significant time reduction. Moreover, the M200 group showed reduced GFAP immunoreactivity in hippocampal dentate gyrus and CA1 compared with the STZ group. STZ mice showed high p-Tau levels, reduced p-CREB, and accumulation of β-amyloid (Aβ) plaque in hippocampal areas and corpus callosum. In contrast, all these changes were reversed in the M200 group. Protein expressions of p-Tau, p-ERK, pGSK3, iNOS, nNOS, PARP, Cytochrome c, caspase 3, and GluN2A were increased in the parietal cortex of STZ mice and significantly counteracted in M200 mice. Moreover, M200 mice also showed significantly high levels of eNOS, AMPK, and p-AKT expression. In conclusion, metformin improved spatial memory in diabetic mice, which can be associated with reducing p-Tau and β-amyloid (Aβ) plaque load and inhibition of neuronal death.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Advani A, Connelly KA, Advani SL et al (2013) Role of the eNOS-NO system in regulating the antiproteinuric effects of VEGF receptor 2 inhibition in diabetes. Biomed Res Int 2013:201475. https://doi.org/10.1155/2013/201475
Alberdi E, Sánchez-Gómez MV, Cavaliere F et al (2010) Amyloid β oligomers induce Ca2+ dysregulation and neuronal death through activation of ionotropic glutamate receptors. Cell Calcium 47:264–272. https://doi.org/10.1016/j.ceca.2009.12.010
Allard JS, Perez EJ, Fukui K et al (2016) Prolonged metformin treatment leads to reduced transcription of Nrf2 and neurotrophic factors without cognitive impairment in older C57BL/6J mice. Behav Brain Res 301:1–9. https://doi.org/10.1016/j.bbr.2015.12.012
Alvarez EO, Beauquis J, Revsin Y et al (2009) Cognitive dysfunction and hippocampal changes in experimental type 1 diabetes. Behav Brain Res 198:224–230. https://doi.org/10.1016/j.bbr.2008.11.001
Arrick DM, Sharpe GM, Sun H, Mayhan WG (2007) Diabetes-induced cerebrovascular dysfunction: role of poly(ADP-ribose) polymerase. Microvasc Res 73:1–6. https://doi.org/10.1016/j.mvr.2006.08.001
Aulston BD, Odero GL, Zaid A, Glazner GW (2013) Alzheimer’s Disease and Diabetes. In: Zerr I (ed) Understanding Alzheimer’s Disease. InTech
Ba X, Garg NJ (2011) Signaling mechanism of poly(ADP-ribose) polymerase-1 (PARP-1) in inflammatory diseases. Am J Pathol 178:946–955
Bedse G, Di Domenico F, Serviddio G, Cassano T (2015) Aberrant insulin signaling in Alzheimer’s disease: current knowledge. Front Neurosci 9:1–13. https://doi.org/10.3389/fnins.2015.00204
Bélanger M, Allaman I, Magistretti PJ (2011) Brain energy metabolism: focus on astrocyte-neuron metabolic cooperation. Cell Metab 14:724–738. https://doi.org/10.1016/j.cmet.2011.08.016
Blázquez E, Velázquez E, Hurtado-Carneiro V, Ruiz-Albusac JM (2014) Insulin in the brain: its pathophysiological implications for States related with central insulin resistance, type 2 diabetes and Alzheimer’s disease. Front Endocrinol (lausanne) 5:161. https://doi.org/10.3389/fendo.2014.00161
Bradford MM (1976) A rapid and sensitive method for the quantiWcation of microgram quantities of protein utilizing the principle of protein– dye binding. Anal Biochem 72:248–254. https://doi.org/10.1016/0003-2697(76)90527-3
Calabrese V, Mancuso C, Calvani M et al (2007) Nitric oxide in the central nervous system: neuroprotection versus neurotoxicity. Nat Rev Neurosci 8:766–775. https://doi.org/10.1038/nrn2214
Chami B, Steel AJ, De La Monte SM, Sutherland GT (2016) The rise and fall of insulin signaling in Alzheimer’s disease. Metab Brain Dis 31:497–515. https://doi.org/10.1007/s11011-016-9806-1
Chaudhari K, Reynolds CD, Yang SH (2020) Metformin and cognition from the perspectives of sex, age, and disease. GeroScience 42:97–116. https://doi.org/10.1007/s11357-019-00146-3
Chen Y, Zhou K, Wang R et al (2009) Antidiabetic drug metformin (GlucophageR) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc Natl Acad Sci USA 106:3907–3912. https://doi.org/10.1073/pnas.0807991106
Cheng C, Lin C-H, Tsai Y-W et al (2014) Type 2 diabetes and antidiabetic medications in relation to dementia diagnosis. J Gerontol Ser A 69:1299–1305. https://doi.org/10.1093/gerona/glu073
Chung MM, Nicol CJ, Cheng YC et al (2017) Metformin activation of AMPK suppresses AGE-induced inflammatory response in hNSCs. Exp Cell Res 352:75–83. https://doi.org/10.1016/j.yexcr.2017.01.017
Clark GJ, Pandya K, Lau-Cam CA (2017) The Effect of Metformin and Taurine, Alone and in Combination, on the Oxidative Stress Caused by Diabetes in the Rat Brain. In: Lee D-H, Schaffer SW, Park E, Kim HW (eds). Springer Netherlands, Dordrecht, pp 353–369
Correia S, Carvalho C, Santos MS et al (2008) Mechanisms of action of metformin in Type 2 diabetes and associated complications : an overview. Mini-Rev Med Chem 8:1343–1354 ((1389-5575/08 $55.00+.00))
Dawson VL, Dawson TM (2004) Deadly conversations: nuclear-mitochondrial cross-talk. J Bioenerg Biomembr 36:287–294. https://doi.org/10.1023/B:JOBB.0000041755.22613.8d
Dawson TM, Dawson VL (2018) Nitric Oxide Signaling in Neurodegeneration and Cell Death. In: Advances in Pharmacology, 1st edn. Elsevier Inc., pp 57–83
Derkach KV, Kuznetsova LA, Sharova TS et al (2015) the effects of long-term metformin treatment on the activity of adenylyl cyclase system and no-synthases in the brain and the myocardium of rats with obesity. Tsitologiia 57:360–369. https://doi.org/10.1134/S1990519X1505003X
Devi L, Alldred MJ, Ginsberg SD, Ohno M (2012) Mechanisms underlying insulin deficiency-induced acceleration of β-amyloidosis in a mouse model of Alzheimer’s Disease. PLoS ONE 7:e32792. https://doi.org/10.1371/journal.pone.0032792
Evans JL, Goldfine ID, Maddux BA, Grodsky GM (2003) Are oxidative stress activated signaling pathways mediators of insulin resistance and B-cell dysfunction? Diabetes 52:1–8
Folch J, Ettcheto M, Busquets O et al (2018) The implication of the brain insulin receptor in late onset Alzheimer’s disease dementia. Pharmaceuticals 11:1–16. https://doi.org/10.3390/ph11010011
Frost GR, Li YM (2017) The role of astrocytes in amyloid production and Alzheimer’s disease. Open Biol 7:1–14. https://doi.org/10.1098/rsob.170228
Garthwaite J, Boulton CL (1995) Nitric oxide signaling in the central nervous system. Annu Rev Physiol 57:683–706. https://doi.org/10.1146/annurev.ph.57.030195.003343
Giansanti V, Donà F, Tillhon M, Scovassi AI (2010) PARP inhibitors: new tools to protect from inflammation. Biochem Pharmacol 80:1869–1877
Green LC, Wagner DA, Glogowski J et al (1982) Analysis of nitrate, nitrite, and [15N ] nitrate in biological fluids automated NO; and NO ? analysis. Analysis 126:131–138
Haroon E, Fleischer CC, Felger JC et al (2016) Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Mol Psychiatry 21:1351–1357. https://doi.org/10.1038/mp.2015.206
Harris JA, Devidze N, Verret L et al (2010) Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron 68:428–441. https://doi.org/10.1016/j.neuron.2010.10.020
Hayden MS, Ghosh S (2008) Shared principles in NF-κB signaling. Cell 132:344–362. https://doi.org/10.1016/j.cell.2008.01.020
He L, Chang E, Peng J et al (2016) Activation of the cAMP-PKA pathway antagonizes metformin suppression of hepatic glucose production. J Biol Chem 291:10562–10570. https://doi.org/10.1074/jbc.M116.719666
Ismaiel AAK, Espinosa-Oliva AM, Santiago M et al (2016) Metformin, besides exhibiting strong in vivo anti-inflammatory properties, increases mptp-induced damage to the nigrostriatal dopaminergic system. Toxicol Appl Pharmacol 298:19–30. https://doi.org/10.1016/j.taap.2016.03.004
Ittner LM, Ke YD, Delerue F et al (2010) Dendritic function of tau mediates amyloid-β toxicity in alzheimer’s disease mouse models. Cell 142:387–397. https://doi.org/10.1016/j.cell.2010.06.036
Jangra A, Datusalia AK, Sharma SS (2014) Reversal of neurobehavioral and neurochemical alterations in STZ-induced diabetic rats by FeTMPyP, a peroxynitrite decomposition catalyst and 1,5-Isoquinolinediol a poly(ADP-ribose) polymerase inhibitor. Neurol Res 36:619–626. https://doi.org/10.1179/1743132813Y.0000000301
Jayanarayanan S, Smijin S, Peeyush KT et al (2013) NMDA and AMPA receptor mediated excitotoxicity in cerebral cortex of streptozotocin induced diabetic rat: ameliorating effects of curcumin. Chem Biol Interact 201:39–48. https://doi.org/10.1016/j.cbi.2012.11.024
Jing YH, Chen KH, Kuo PC et al (2013) Neurodegeneration in streptozotocin-induced diabetic rats is attenuated by treatment with resveratrol. Neuroendocrinology 98:116–127. https://doi.org/10.1159/000350435
Jolivalt CG, Lee CA, Beiswenger KK et al (2008) 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 86:3265–3274. https://doi.org/10.1002/jnr.21787
Jolivalt CG, Hurford R, Lee C, a, et al (2010) Type 1 diabetes exaggerates features of Alzheimer’s disease in APP transgenic mice. Exp Neurol 223:422–431. https://doi.org/10.1016/j.expneurol.2009.11.005
Kim YW, Park SY, Kim JY et al (2007) Metformin restores the penile expression of nitric oxide synthase in high-fat-fed obese rats. J Androl 28:555–560. https://doi.org/10.2164/jandrol.106.001602
Knowles RG, Moncada S (1994) Nitric oxide synthases in mammals. Biochem J 298:249–258. https://doi.org/10.1042/bj2980249
Koenig AM, Mechanic-Hamilton D, Xie SX et al (2017) Effects of the insulin sensitizer metformin in Alzheimer disease. Alzheimer Dis Assoc Disord 31:107–113. https://doi.org/10.1097/WAD.0000000000000202
Łabuzek K, Liber S, Gabryel B et al (2010a) Ambivalent effects of compound C (dorsomorphin) on inflammatory response in LPS-stimulated rat primary microglial cultures. Naunyn Schmiedebergs Arch Pharmacol 381:41–57. https://doi.org/10.1007/s00210-009-0472-2
Łabuzek K, Liber S, Gabryel B, Okopień B (2010b) Metformin has adenosine-monophosphate activated protein kinase (AMPK)-independent effects on LPS-stimulated rat primary microglial cultures. Pharmacol Rep 62:827–848. https://doi.org/10.1016/S1734-1140(10)70343-1
Lee JH, Jahrling JB, Denner L, Dineley KT (2018) Targeting insulin for Alzheimer’s disease: mechanisms, status and potential directions. J Alzheimer’s Dis 64:S427–S453. https://doi.org/10.3233/JAD-179923
Malinski T (2007) Nitric oxide and nitroxidative stress in Alzheimer’s disease. J Alzheimers Dis 11:207–218
Manucha W (2017) Mitochondrial dysfunction associated with nitric oxide pathways in glutamate neurotoxicity. Clínica e Investig En Arterioscler 29:92–97. https://doi.org/10.1016/j.arteri.2016.04.002
Miller RA, Chu Q, Xie J et al (2013) Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494:256–260. https://doi.org/10.1038/nature11808
Morris M, Maeda S, Vossel K, Mucke L (2011) The Many Faces of Tau. Neuron 70:410–426. https://doi.org/10.1016/j.neuron.2011.04.009
Moshage H, Kok B, Huizenga JR, Jansen PLM (1995) Nitrite and nitrate determinations in plasma: a critical evaluation. Clin Chem 41:892–896
Mostafa DK, Ismail CA, Ghareeb DA (2016) Differential metformin dose-dependent effects on cognition in rats: role of Akt. Psychopharmacology 233:2513–2524. https://doi.org/10.1007/s00213-016-4301-2
Murphy S (2000) Production of nitric oxide by glial cells: Regulation and potential roles in the CNS. Glia 29:1–13
Nagayach A, Patro N, Patro I (2014) Astrocytic and microglial response in experimentally induced diabetic rat brain. Metab Brain Dis 29:747–761. https://doi.org/10.1007/s11011-014-9562-z
Nakazawa T, Komai S, Tezuka T et al (2001) Characterization of Fyn-mediated tyrosine phosphorylation sites on GluRε2 (NR2B) Subunit of the N-Methyl-d-aspartate receptor. J Biol Chem 276:693–699. https://doi.org/10.1074/jbc.M008085200
Nedergaard M, Dirnagl U (2005) Role of glial cells in cerebral ischemia. Glia 50:281–286. https://doi.org/10.1002/glia.20205
Oliveira WH, Nunes AK, França MER et al (2016) Effects of metformin on inflammation and short-term memory in streptozotocin-induced diabetic mice. Brain Res 1644:149–160. https://doi.org/10.1016/j.brainres.2016.05.013
Ou Z, Kong X, Sun X et al (2018) Metformin treatment prevents amyloid plaque deposition and memory impairment in APP/PS1 mice. Brain Behav Immun 69:351–363. https://doi.org/10.1016/j.bbi.2017.12.009
Pekny M, Wilhelmsson U, Pekna M (2014) The dual role of astrocyte activation and reactive gliosis. Neurosci Lett 565:30–38. https://doi.org/10.1016/j.neulet.2013.12.071
Peng Y, Liu J, Shi L et al (2016) Mitochondrial dysfunction precedes depression of AMPK/AKT signaling in insulin resistance induced by high glucose in primary cortical neurons. J Neurochem. https://doi.org/10.1111/jnc.13563
Pickering RJ, Rosado CJ, Sharma A et al (2018) Recent novel approaches to limit oxidative stress and inflammation in diabetic complications. Clin Transl Immunol 7:1–20. https://doi.org/10.1002/cti2.1016
Picone P, Nuzzo D, Caruana L et al (2015) Metformin increases APP expression and processing via oxidative stress, mitochondrial dysfunction and NF-??B activation: use of insulin to attenuate metformin’s effect. Biochim Biophys Acta Mol Cell Res 1853:1046–1059. https://doi.org/10.1016/j.bbamcr.2015.01.017
Planel E, Tatebayashi Y, Miyasaka T et al (2007) Insulin dysfunction induces in vivo tau hyperphosphorylation through distinct mechanisms. J Neurosci 27:13635–13648. https://doi.org/10.1523/JNEUROSCI.3949-07.2007
Pooler AM, Polydoro M, Maury EA et al (2015) Amyloid accelerates tau propagation and toxicity in a model of early Alzheimer’s disease. Acta Neuropathol Commun 3:14. https://doi.org/10.1186/s40478-015-0199-x
Reihill JA, Ewart MA, Hardie DG, Salt IP (2007) AMP-activated protein kinase mediates VEGF-stimulated endothelial NO production. Biochem Biophys Res Commun 354:1084–1088. https://doi.org/10.1016/j.bbrc.2007.01.110
Rocha SWS, de França MER, Rodrigues GB et al (2014) Diethylcarbamazine reduces chronic inflammation and fibrosis in carbon tetrachloride- (CCl 4 -) induced liver injury in mice. Mediators Inflamm 2014:1–15. https://doi.org/10.1155/2014/696383
Rong Y, Lu X, Bernard A et al (2008) Tyrosine phosphorylation of ionotropic glutamate receptors by Fyn or Src differentially modulates their susceptibility to calpain and enhances their binding to spectrin and PSD-95. J Neurochem 79:382–390. https://doi.org/10.1046/j.1471-4159.2001.00565.x
Seung TW, Park SK, Kang JY et al (2018) Ethyl acetate fraction from Hibiscus sabdariffa L. attenuates diabetes-associated cognitive impairment in mice. Food Res Int 105:589–598. https://doi.org/10.1016/j.foodres.2017.11.063
Shieh JCC, Huang PT, Lin YF (2020) Alzheimer’s disease and diabetes: insulin signaling as the bridge linking two pathologies. Mol Neurobiol 57:1966–1977. https://doi.org/10.1007/s12035-019-01858-5
Shokrzadeh M, Mirshafa A, Yekta Moghaddam N et al (2018) Mitochondrial dysfunction contribute to diabetic neurotoxicity induced by streptozocin in mice: protective effect of Urtica dioica and pioglitazone. Toxicol Mech Methods 28:499–506. https://doi.org/10.1080/15376516.2018.1459993
Sima AAF, Zhang W, Kreipke CW et al (2009) Inflammation in diabetic encephalopathy is prevented by C-peptide. Rev Diabet Stud 6:37–42. https://doi.org/10.1900/RDS.2009.6.37
Tai H-C, Serrano-Pozo A, Hashimoto T et al (2012) The synaptic accumulation of hyperphosphorylated tau oligomers in alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol 181:1426–1435. https://doi.org/10.1016/j.ajpath.2012.06.033
Tai H-C, Wang BY, Serrano-Pozo A et al (2014) Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer’s disease. Acta Neuropathol Commun 2:146. https://doi.org/10.1186/s40478-014-0146-2
van der Harg JM, Eggels L, Bangel FN et al (2017) Insulin deficiency results in reversible protein kinase A activation and tau phosphorylation. Neurobiol Dis 103:163–173. https://doi.org/10.1016/j.nbd.2017.04.005
Vanhoutte PM, Shimokawa H, Tang EHC, Feletou M (2009) Endothelial dysfunction and vascular disease. Acta Physiol 196:193–222. https://doi.org/10.1111/j.1748-1716.2009.01964.x
Wang X, Zheng W, Xie J-W et al (2010) Insulin deficiency exacerbates cerebral amyloidosis and behavioral deficits in an Alzheimer transgenic mouse model. Mol Neurodegener 5:46. https://doi.org/10.1186/1750-1326-5-46
Wang J, Gallagher D, Devito LM et al (2012) Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 11:23–35. https://doi.org/10.1016/j.stem.2012.03.016
Whiting DR, Guariguata L, Weil C, Shaw J (2011) IDF Diabetes Atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 94:311–321. https://doi.org/10.1016/j.diabres.2011.10.029
Wu H-Y, Kuo P-C, Wang Y-T et al (2018) β-amyloid induces pathology-related patterns of tau hyperphosphorylation at synaptic terminals. J Neuropathol Exp Neurol 77:814–826. https://doi.org/10.1093/jnen/nly059
Xia N, Förstermann U, Li H (2014) Resveratrol and endothelial nitric oxide. Molecules 19:16102–16121. https://doi.org/10.3390/molecules191016102
Zempel H, Thies E, Mandelkow E, Mandelkow E-M (2010) A oligomers cause localized Ca2+ elevation, missorting of endogenous tau into dendrites, tau phosphorylation, and destruction of microtubules and spines. J Neurosci 30:11938–11950. https://doi.org/10.1523/JNEUROSCI.2357-10.2010
Zhang CX, Pan SN, Sen MR et al (2011) Metformin attenuates ventricular hypertrophy by activating the AMP-activated protein kinase-endothelial nitric oxide synthase pathway in rats. Clin Exp Pharmacol Physiol 38:55–62. https://doi.org/10.1111/j.1440-1681.2010.05461.x
Zhou X, Wang H, Burg MB, Ferraris JD (2013) Inhibitory phosphorylation of GSK-3β by AKT, PKA, and PI3K contributes to high NaCl-induced activation of the transcription factor NFAT5 (TonEBP/OREBP). Am J Physiol Physiol 304:F908–F917. https://doi.org/10.1152/ajprenal.00591.2012
Zhou W, Kavelaars A, Heijnen CJ (2016) Metformin prevents cisplatin-induced cognitive impairment and brain damage in mice. PLoS ONE 11:e0151890. https://doi.org/10.1371/journal.pone.0151890
Funding
The authors would like to thank the following Brazilian foundations for financial support: Oswaldo Cruz Foundation of Pernambuco (FIOCRUZ-PE), the Institute of Science and Technology on Neuroimmunomodulation (INCT-NIM; # 465489/2014–1), and National Council for Scientific and Technological Development (CNPq;#301777/2012–8) for research support. This study was financed in part by the Coordination of Improvement of Higher Education Personnel—Brazil (CAPES), and Foundation of Support to Science and Technology of State of Pernambuco (FACEPE; #AMD-0180–2.00/16).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that there is no conflict of interest.
Academic linkage
This article is part of the doctoral thesis of Wilma Helena Oliveira, a student at the Federal University of Pernambuco – UFPE.
Additional information
Communicated by Sreedharan Sajikumar.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Oliveira, W.H., Braga, C.F., Lós, D.B. et al. Metformin prevents p-tau and amyloid plaque deposition and memory impairment in diabetic mice. Exp Brain Res 239, 2821–2839 (2021). https://doi.org/10.1007/s00221-021-06176-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00221-021-06176-8