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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

Exendin-4 Improves Cognitive Function of Diabetic Mice via Increasing Brain Insulin Synthesis

Author(s): Xuemin Peng, Xiaoli Shi, Jiaojiao Huang, Shujun Zhang, Yongli Yan, Delin Ma, Weijie Xu, Weijie Xu, Kun Dong, Jing Tao, Mengni Li and Yan Yang*

Volume 18, Issue 7, 2021

Published on: 29 September, 2021

Page: [546 - 557] Pages: 12

DOI: 10.2174/1567205018666210929150004

Price: $65

Abstract

Background and Objective: Type 2 Diabetes (T2D) patients are more prone to develop Alzheimer’s Disease (AD). We have previously shown that Glucagon-like peptide-1 receptor agonist exendin-4 (Ex-4) reduces tau hyperphosphorylation in T2D animals through upregulating insulin signaling, and peripheral injected Ex-4 increases insulin levels in the T2D brain. This study aims to further clarify whether the elevated insulin in the brain is produced by nerve cells under the action of Ex-4.

Methods: The neuronal cell line-HT22 was treated with Ex-4 under high glucose or normal cultivation, and the number of insulin-positive cells as well as the expression levels of insulin synthesis-related genes were examined. The db/db mice were treated with the peripheral injection of Ex-4 and/or IntraCerebroVentricular (ICV) injection of siRNA to inhibit the expression of insulin synthesis- related genes and the behavior tests were carried on. Finally, plasma glucose, Cerebrospinal Fluid (CSF) glucose, CSF insulin, phosphorylation of tau, phosphorylation of AKT and GSK-3β of db/db mice were detected.

Results: We found that Ex-4 promoted the expression of insulin synthesis-related genes and induced an obvious increase of insulin-positive HT-22 neuronal cells in a high glucose environment. Peripheral injection of Ex-4 improved the cognitive function of db/db mice and increased brain insulin levels which activated brain insulin signaling and subsequently alleviated tau hyperphosphorylation. However, when siRNA-neurod1 was injected to block insulin synthesis, the cognitive function of db/db mice was not improved under the action of Ex-4 anymore. Moreover, the brain insulin levels dropped to an extremely low level, and the phosphorylation level of tau increased significantly.

Conclusion: This study demonstrated that Ex-4 improved cognition function by promoting brain insulin synthesis followed by the activation of brain insulin signaling and alleviation of tau hyperphosphorylation.

Keywords: Type 2 diabetes, Alzheimer's disease, glucagon-like peptide-1, insulin, exendin-4, db/db.

« Previous Next »
[1]
Stranahan AM, Mattson MP. Metabolic reserve as a determinant of cognitive aging. J Alzheimers Dis 2012; 30(Suppl. 2): S5-S13.
[http://dx.doi.org/10.3233/JAD-2011-110899] [PMID: 22045480]
[2]
Iqbal K, Liu F, Gong CX, Grundke-Iqbal I. Tau in Alzheimer disease and related tauopathies. Curr Alzheimer Res 2010; 7(8): 656-64.
[http://dx.doi.org/10.2174/156720510793611592] [PMID: 20678074]
[3]
Noble W, Hanger DP, Miller CC, Lovestone S. The importance of tau phosphorylation for neurodegenerative diseases. Front Neurol 2013; 4: 83.
[http://dx.doi.org/10.3389/fneur.2013.00083] [PMID: 23847585]
[4]
Tolppanen AM, Lavikainen P, Solomon A, et al. History of medically treated diabetes and risk of Alzheimer disease in a nationwide case-control study. Diabetes Care 2013; 36(7): 2015-9.
[http://dx.doi.org/10.2337/dc12-1287] [PMID: 23340883]
[5]
Xue M, Xu W, Ou YN, et al. Diabetes mellitus and risks of cognitive impairment and dementia: A systematic review and meta-analysis of 144 prospective studies. Ageing Res Rev 2019; 55: 100944.
[http://dx.doi.org/10.1016/j.arr.2019.100944] [PMID: 31430566]
[6]
Yuan XY, Wang XG. Mild cognitive impairment in type 2 diabetes mellitus and related risk factors: a review. Rev Neurosci 2017; 28(7): 715-23.
[http://dx.doi.org/10.1515/revneuro-2017-0016] [PMID: 28704200]
[7]
De Felice FG, Ferreira ST. Inflammation, defective insulin signaling, and mitochondrial dysfunction as common molecular denominators connecting type 2 diabetes to Alzheimer disease. Diabetes 2014; 63(7): 2262-72.
[http://dx.doi.org/10.2337/db13-1954] [PMID: 24931033]
[8]
Tumminia A, Vinciguerra F, Parisi M, Frittitta L. Type 2 diabetes mellitus and Alzheimer’s disease: Role of insulin signalling and therapeutic implications. Int J Mol Sci 2018; 19(11): E3306.
[http://dx.doi.org/10.3390/ijms19113306] [PMID: 30355995]
[9]
Biessels GJ, Reagan LP. Hippocampal insulin resistance and cognitive dysfunction. Nat Rev Neurosci 2015; 16(11): 660-71.
[http://dx.doi.org/10.1038/nrn4019] [PMID: 26462756]
[10]
Bhat NR, Thirumangalakudi L. Increased tau phosphorylation and impaired brain insulin/IGF signaling in mice fed a high fat/high cholesterol diet. J Alzheimers Dis 2013; 36(4): 781-9.
[http://dx.doi.org/10.3233/JAD-2012-121030] [PMID: 23703152]
[11]
Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer’s disease and diabetes. J Pathol 2011; 225(1): 54-62.
[http://dx.doi.org/10.1002/path.2912] [PMID: 21598254]
[12]
Yang Y, Zhang J, Ma D, et al. Subcutaneous administration of liraglutide ameliorates Alzheimer-associated tau hyperphosphorylation in rats with type 2 diabetes. J Alzheimers Dis 2013; 37(3): 637-48.
[http://dx.doi.org/10.3233/JAD-130491] [PMID: 23948890]
[13]
Havrankova J, Schmechel D, Roth J, Brownstein M. Identification of insulin in rat brain. Proc Natl Acad Sci USA 1978; 75(11): 5737-41.
[http://dx.doi.org/10.1073/pnas.75.11.5737] [PMID: 364489]
[14]
Kleinridders A, Ferris HA, Cai W, Kahn CR. Insulin action in brain regulates systemic metabolism and brain function. Diabetes 2014; 63(7): 2232-43.
[http://dx.doi.org/10.2337/db14-0568] [PMID: 24931034]
[15]
Kuwabara T, Kagalwala MN, Onuma Y, et al. Insulin biosynthesis in neuronal progenitors derived from adult hippocampus and the olfactory bulb. EMBO Mol Med 2011; 3(12): 742-54.
[http://dx.doi.org/10.1002/emmm.201100177] [PMID: 21984534]
[16]
Hamilton A, Patterson S, Porter D, Gault VA, Holscher C. Novel GLP-1 mimetics developed to treat type 2 diabetes promote progenitor cell proliferation in the brain. J Neurosci Res 2011; 89(4): 481-9.
[http://dx.doi.org/10.1002/jnr.22565] [PMID: 21312223]
[17]
Perry T, Greig NH. The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer’s disease. J Alzheimers Dis 2002; 4(6): 487-96.
[http://dx.doi.org/10.3233/JAD-2002-4605] [PMID: 12515900]
[18]
Hunter K, Hölscher C. Drugs developed to treat diabetes, liraglutide and lixisenatide, cross the blood brain barrier and enhance neurogenesis. BMC Neurosci 2012; 13: 33.
[http://dx.doi.org/10.1186/1471-2202-13-33] [PMID: 22443187]
[19]
Ma DL, Chen FQ, Xu WJ, Yue WZ, Yuan G, Yang Y. Early intervention with glucagon-like peptide 1 analog liraglutide prevents tau hyperphosphorylation in diabetic db/db mice. J Neurochem 2015; 135(2): 301-8.
[http://dx.doi.org/10.1111/jnc.13248] [PMID: 26183127]
[20]
Yang Y, Ma D, Xu W, et al. Exendin-4 reduces tau hyperphosphorylation in type 2 diabetic rats via increasing brain insulin level. Mol Cell Neurosci 2016; 70: 68-75.
[http://dx.doi.org/10.1016/j.mcn.2015.10.005] [PMID: 26640240]
[21]
Yang Y, Moghadam AA, Cordner ZA, Liang NC, Moran TH. Long term exendin-4 treatment reduces food intake and body weight and alters expression of brain homeostatic and reward markers. Endocrinology 2014; 155(9): 3473-83.
[http://dx.doi.org/10.1210/en.2014-1052] [PMID: 24949661]
[22]
Yang Y, Choi PP, Smith WW, et al. Exendin-4 reduces food intake via the PI3K/AKT signaling pathway in the hypothalamus. Sci Rep 2017; 7(1): 6936.
[http://dx.doi.org/10.1038/s41598-017-06951-0] [PMID: 28761132]
[23]
Chawla A, Cordner ZA, Boersma G, Moran TH. Cognitive impairment and gene expression alterations in a rodent model of binge eating disorder. Physiol Behav 2017; 180: 78-90.
[http://dx.doi.org/10.1016/j.physbeh.2017.08.004] [PMID: 28821448]
[24]
Maia LF, Kaeser SA, Reichwald J, et al. Changes in amyloid-β and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci Transl Med 2013; 5(194): 194re2.
[http://dx.doi.org/10.1126/scitranslmed.3006446] [PMID: 23863834]
[25]
Mullins RJ, Mustapic M, Chia CW, et al. A pilot study of exenatide actions in Alzheimer’s disease. Curr Alzheimer Res 2019; 16(8): 741-52.
[http://dx.doi.org/10.2174/1567205016666190913155950] [PMID: 31518224]
[26]
Li Y, Chigurupati S, Holloway HW, et al. Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis. PLoS One 2012; 7(2): e32008.
[http://dx.doi.org/10.1371/journal.pone.0032008] [PMID: 22384126]
[27]
Li Y, Perry T, Kindy MS, et al. GLP-1 receptor stimulation preserves primary cortical and dopaminergic neurons in cellular and rodent models of stroke and Parkinsonism. Proc Natl Acad Sci USA 2009; 106(4): 1285-90.
[http://dx.doi.org/10.1073/pnas.0806720106] [PMID: 19164583]
[28]
Greig NH, Tweedie D, Rachmany L, et al. Incretin mimetics as pharmacologic tools to elucidate and as a new drug strategy to treat traumatic brain injury. Alzheimers Dement 2014; 10(1)(Suppl.): S62-75.
[http://dx.doi.org/10.1016/j.jalz.2013.12.011] [PMID: 24529527]
[29]
Devaskar SU, Giddings SJ, Rajakumar PA, Carnaghi LR, Menon RK, Zahm DS. Insulin gene expression and insulin synthesis in mammalian neuronal cells. J Biol Chem 1994; 269(11): 8445-54.
[http://dx.doi.org/10.1016/S0021-9258(17)37214-9] [PMID: 8132571]
[30]
Conrad E, Stein R, Hunter CS. Revealing transcription factors during human pancreatic β cell development. Trends Endocrinol Metab 2014; 25(8): 407-14.
[http://dx.doi.org/10.1016/j.tem.2014.03.013] [PMID: 24831984]
[31]
Schiöth HB, Craft S, Brooks SJ, Frey WH II, Benedict C. Brain insulin signaling and Alzheimer’s disease: current evidence and future directions. Mol Neurobiol 2012; 46(1): 4-10.
[http://dx.doi.org/10.1007/s12035-011-8229-6] [PMID: 22205300]
[32]
Yang Y, Ma D, Wang Y, et al. Intranasal insulin ameliorates tau hyperphosphorylation in a rat model of type 2 diabetes. J Alzheimers Dis 2013; 33(2): 329-38.
[http://dx.doi.org/10.3233/JAD-2012-121294] [PMID: 22936005]
[33]
McNay EC, Recknagel AK. Brain insulin signaling: a key component of cognitive processes and a potential basis for cognitive impairment in type 2 diabetes. Neurobiol Learn Mem 2011; 96(3): 432-42.
[http://dx.doi.org/10.1016/j.nlm.2011.08.005] [PMID: 21907815]
[34]
Claxton A, Baker LD, Hanson A, et al. Long-acting intranasal insulin detemir improves cognition for adults with mild cognitive impairment or early-stage Alzheimer’s disease dementia. J Alzheimers Dis 2015; 44(3): 897-906.
[http://dx.doi.org/10.3233/JAD-141791] [PMID: 25374101]
[35]
Freiherr J, Hallschmid M, Frey WH II, et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 2013; 27(7): 505-14.
[http://dx.doi.org/10.1007/s40263-013-0076-8] [PMID: 23719722]
[36]
Hernandez F, Lucas JJ, Avila J. GSK3 and tau: two convergence points in Alzheimer’s disease. J Alzheimers Dis 2013; 33(Suppl. 1): S141-4.
[http://dx.doi.org/10.3233/JAD-2012-129025] [PMID: 22710914]

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