Strong Association of Serum GSK-3β/BDNF Ratio with Mild Cognitive Impairment in Elderly Type 2 Diabetic Patients

Author(s): Bingying Du, Yongjie Lian, Chao Chen, Hailing Zhang, Yueping Bi, Cunxiu Fan*, Xiaoying Bi*

Journal Name: Current Alzheimer Research

Volume 16 , Issue 12 , 2019

  Journal Home
Translate in Chinese
Become EABM
Become Reviewer
Call for Editor


Background: Glycogen Synthase Kinase (GSK)-3β and Brain-derived Neurotrophic Factor (BDNF) play vital roles in both Mild Cognitive Impairment (MCI) and Type 2 Diabetes Mellitus (T2DM). The underlying mechanisms may involve inflammation and oxidative stress.

Objectives: To investigate the association of the GSK-3β/BDNF ratio with MCI in elderly patients with T2DM and whether GSK-3β/BDNF ratio can serve as a new diagnostic biomarker for MCI in comorbid with T2DM (MD).

Methods: A total of 326 old Chinese T2DM patients were included and stratified according to cognition and GSK-3β/BDNF ratio quartiles. MCI was diagnosed according to the National Institute on Aging Alzheimer’s Association workgroups criteria. In addition to routine hematuria and biochemical examinations, Montreal Cognitive Assessment (MoCA) scale was also used to evaluate the cognitive function, and ELISA method was used to measure GSK-3β activity and the serum levels of BDNF, interleukin 1β (IL-1β), high mobility group box-1 (HMGB1) protein, Malonaldehyde (MDA) and 8-isoprostaglandinF2α (8-iso-PGF2α).

Results: We found that GSK-3β activity was negatively correlated with BDNF (r=-0.270, P=0.008), and patients with higher GSK-3β/BDNF ratio had lower MoCA scores (P=0.001). When compared with T2DM patients without MCI (nMD), MD patients had higher GSK-3β activity and GSK-3β/BDNF ratio, but lower BDNF levels. As for inflammation and oxidative stress, IL-1β was inversely correlated with GSK-3β activity, while 8-isoPGF2α was positively correlated with GSK-3β activity and GSK-3β/BDNF ratio. The odds ratio for MCI increased gradually when GSK-3β/BDNF ratio quartile rose from the lowest to the highest (6.90, 95% CI 3.22-14.78). MoCA score was conversely related to GSK-3β/BDNF ratio, age and fast blood glucose (FBG), with GSK-3β/BDNF ratio having the most significant influence on cognition (β=-0.199, P<0.001).

Conclusion: Our data provide evidence for a strong link between GSK-3β/BDNF ratio and MCI. GSK- 3β/BDNF ratio may serve as a better diagnostic biomarker for MD than either GSK-3β or BDNF alone and increased GSK-3β/BDNF ratio indicates a worse cognitive function.

Keywords: Mild cognitive impairment, type 2 diabetes, glycogen synthase kinase-3β, brain-derived neurotrophic factor, inflammation, oxidative stress.

Pu D, Zhao Y, Chen J, Sun Y, Lv A, Zhu S, et al. Protective effects of sulforaphane on cognitive impairments and AD-like lesions in diabetic mice are associated with the upregulation of Nrf2 transcription activity. Neuroscience 381: 35-45. (2018).
Zhai Y, Meng X, Ye T, Xie W, Sun G, Sun X, et al. Inhibiting the NLRP3 inflammasome activation with MCC950 ameliorates diabetic encephalopathy in db/db mice. Molecules 23(3): 522. (2018).
Mariani E, Monastero R, Mecocci P. Mild cognitive impairment: a systematic review. J Alzheimers Dis 12(1): 23-35. (2007).
Grothe M, Heinsen H, Teipel SJ. Atrophy of the cholinergic Basal forebrain over the adult age range and in early stages of Alzheimer’s disease. Biol Psychiatry 71(9): 805-13. (2012).
Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med 256(3): 183-94. (2004).
Arvanitakis Z, Wilson RS, Bienias JL, Evans DA, Bennett DA. Diabetes mellitus and risk of Alzheimer disease and decline in cognitive function. JAMA Neurol 61(5): 661-6. (2004).
Cheng PY, Sy HN, Wu SL, Wang WF, Chen YY. Newly diagnosed type 2 diabetes and risk of dementia: a population-based 7-year follow-up study in Taiwan. J Diabetes Complications 26(5): 382-7. (2012).
Biessels GJ, Strachan MW, Visseren FL, Kappelle LJ, Whitmer RA. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes & Endocrinol 2(3): 246-55. (2014).
Farr SA, Ripley JL, Sultana R, Zhang Z, Niehoff ML, Platt TL, et al. Antisense oligonucleotide against GSK-3beta in brain of SAMP8 mice improves learning and memory and decreases oxidative stress: Involvement of transcription factor Nrf2 and implications for Alzheimer disease. Free Radic Biol Med 67: 387-95. (2014).
Wang H, Kumar A, Lamont RJ. Scott DA3. GSK3beta and the control of infectious bacterial diseases. Trends Microbiol 22(4): 208-17. (2014).
Borror A. Brain-derived neurotrophic factor mediates cognitive improvements following acute exercise. Med Hypotheses 106: 1-5. (2017).
Lucas JJ, Hernández F, Gómez-Ramos P, Morán MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J 20(1-2): 27-39. (2001).
Bhat RV, Budd SL. GSK3beta signalling: casting a wide net in Alzheimer’s disease. Neurosignals 11(5): 251-61. (2002).
Hye A, Kerr F, Archer N, Foy C, Poppe M, Brown R, et al. Glycogen synthase kinase-3 is increased in white cells early in Alzheimer’s disease. Neurosci Lett 373(1): 1-4. (2005).
Forlenza OV, Torres CA, Talib LL, de Paula VJ, Joaquim HP, Diniz BS, et al. Increased platelet GSK3B activity in patients with mild cognitive impairment and Alzheimer’s disease. J Psychiatr Res 45(2): 220-4. (2011).
Hemminqs BA, Yellowlees D, Cohen P. Glycogen synthase KINASE-3 from rabbit skeletal muscle. Methods Enzymol 99: 337-45. (1983).
Ko CY, Wang WL, Wang SM, Chu YY, Chang WC, Wang JM. Glycogen synthase kinase-3beta-mediated CCAAT/enhancer-binding protein delta phosphorylation in astrocytes promotes migration and activation of microglia/macrophages. Neurobiol Aging 35(1): 24-34. (2014).
Cohen P, Goedert M. GSK3 inhibitors: development and therapeutic potential. Nat Rev Drug Discov 3(6): 479-87. (2004).
Xu ZP, Yang SL, Zhao S, Zheng CH, Li HH, et al. Biomarkers for early diagnostic of mild cognitive impairment in type-2 diabetes patients: a multicentre, retrospective, nested case-control study. EBioMedicine 5: 105-13. (2016).
Datusalia AK, Sharma SS. Amelioration of diabetes-induced cognitive deficits by GSK-3beta inhibition is attributed to modulation of neurotransmitters and neuroinflammation. Mol Neurobiol 50(2): 390-405. (2014).
Wang X, Zhao L. Calycosin ameliorates diabetes-induced cognitive impairments in rats by reducing oxidative stress via the PI3K/Akt/GSK-3beta signaling pathway. Biochem Biophys Res Commun 473(2): 428-34. (2016).
Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15(3): 331-7. (2009).
Qin XY, Cao C, Cawley NX, Liu TT, Yuan J, Loh YP, et al. Decreased peripheral brain-derived neurotrophic factor levels in Alzheimer’s disease: a meta-analysis study (N=7277). Mol Psychiatry 22(2): 312-20. (2017).
Krabbe KS, Nielsen AR, Krogh-Madsen R, Plomgaard P, Rasmussen P, Erikstrup C, et al. Brain-derived neurotrophic factor (BDNF) and type 2 diabetes. Diabetologia 50(2): 431-8. (2007).
Boyuk B, Degirmencioglu S, Atalay H, Guzel S, Acar A, Celebi A, et al. Relationship between levels of brain-derived neurotrophic factor and metabolic parameters in patients with type 2 diabetes mellitus. J Diabetes Res 2014978143 (2014).
Eyileten C, Kaplon-Cieslicka A, Mirowska-Guzel D, Malek L, Postula M. Antidiabetic effect of brain-derived neurotrophic factor and its association with inflammation in type 2 diabetes mellitus. Exp Diabetes Res 20172823671 (2017).
Yang W, Dou KF, Song WJ. Prevalence of diabetes among men and women in China. N Engl J Med 362(12): 1090-101. (2010).
O’Driscoll C, Shaikh M. Cross-cultural applicability of the montreal cognitive assessment (MoCA): a systematic review. J Alzheimers Dis 58(3): 789-801. (2017).
Zung WWK. a rating instrument for anxiety disorders. Psychosomatics 12(6): 371-9. (1971).
Yesavage JA, Brink TL, Rose TL, Lum O, Huang V, Adey M, et al. Development and validation of a geriatric depression screening scale: a preliminary report. J Psychiatr Res 17(1): 37-49. (1982).
Albert MS, DeKosky ST, Dickson D, Dubois B, Feldman HH, Fox NC, et al. The diagnosis of mild cognitive impairment due to Alzheimer’s disease: recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 7(3): 270-9. (2011).
Alberti KGMM, Zimmet P. Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus. Provisional report of a WHO Consultation. Diabet Med 15(7): 539-53. (1998).
Hayes AF, Scharkow M. The relative trustworthiness of inferential tests of the indirect effect in statistical mediation analysis: does method really matter? Psychol Sci 24(10): 1918-27. (2013).
Romero-Moreno R, Losada A, Márquez-González M, Mausbach BT. Stressors and anxiety in dementia caregiving: multiple mediation analysis of rumination, experiential avoidance, and leisure. Int Psychogeriatr 28(11): 1835-44. (2016).
Xu ZP, Gan GS, Liu YM, Xiao JS, Liu HX, Mei B, et al. Adiponectin attenuates streptozotocin-induced tau hyperphosphorylation and cognitive deficits by rescuing PI3K/Akt/GSK-3beta Pathway. Neurochem Res 43(2): 316-23. (2018).
Shimada H, Makizako H, Doi T, Yoshida D, Tsutsumimoto K, Anan Y, et al. A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. Front Aging Neurosci 6: 69. (2014).
Zheng T, Liu H, Qin L, Chen B, Zhang X, Hu X, et al. Oxidative stress-mediated influence of plasma DPP4 activity to BDNF ratio on mild cognitive impairment in elderly type 2 diabetic patients: results from the GDMD study in China. Metabolism 87: 105-12. (2018).
Gao C, Hölscher C, Liu Y, Li L. GSK3: a key target for the development of novel treatments for type 2 diabetes mellitus and Alzheimer disease. Rev Neurosci 23(1): 1-11. (2011).
Price JB, Bronars C, Erhardt S, Cullen KR, Schwieler L, Berk M, et al. Bioenergetics and synaptic plasticity as potential targets for individualizing treatment for depression. Neurosci Biobehav Rev 90: 212-20. (2018).
Dursun E, Gezen-Ak D, Hanağası H, Bilgiç B, Lohmann E, Ertan S, et al. The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer’s disease, mild cognitive impairment or Parkinson’s disease. J Neuroimmunol 283: 50-7. (2015).
Tian S, Huang R, Han J, Cai R, Guo D, Lin H, et al. Increased plasma Interleukin-1beta level is associated with memory deficits in type 2 diabetic patients with mild cognitive impairment. Psychoneuroendocrinology 96: 148-54. (2018).
Duan Q, Sun W, Yuan H, Mu X. MicroRNA-135b-5p prevents oxygen-glucose deprivation and reoxygenation-induced neuronal injury through regulation of the GSK-3beta/Nrf2/ARE signaling pathway. Arch Med Sci 14(4): 735-44. (2018).
Şirin FB, Kumbul Doğuç D, Vural H, Eren I, Inanli I, Sütçü R, et al. Plasma 8-isoPGF2α and serum melatonin levels in patients with minimal cognitive impairment and Alzheimer disease. Turk J Med Sci 45(5): 1073-7. (2015).

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Published on: 26 August, 2019
Page: [1151 - 1160]
Pages: 10
DOI: 10.2174/1567205016666190827112546
Price: $65

Article Metrics

PDF: 28