Interplay between Alzheimer’s disease and global glucose metabolism revealed by the metabolic profile alterations of pancreatic tissue and serum in APP/PS1 transgenic mice

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Increasing evidence suggests that there is a correlation between type 2 diabetes mellitus (T2D) and Alzheimer’s disease (AD). Increased Aβ polypeptide production in AD patients would promote metabolic abnormalities, insulin signaling dysfunction and perturbations in glucose utilization, thus leading to the onset of T2D. However, the metabolic mechanisms underlying the interplay between AD and its diabetes-promoting effects are not fully elucidated. Particularly, systematic metabolomics analysis has not been performed for the pancreas tissues of AD subjects, which play key roles in the glucose metabolism of living systems. In the current study, we characterized the dynamic metabolic profile alterations of the serum and the pancreas of APP/PS1 double-transgenic mice (an AD mouse model) using the untargeted metabolomics approaches. Serum and pancreatic tissues of APP/PS1 transgenic mice and wild-type mice were extracted and subjected to NMR analysis to evaluate the functional state of pancreas in the progress of AD. Multivariate analysis of principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were conducted to define the global and the local (pancreas) metabolic features associated with the possible initiation of T2D in the progress of AD. Our results showed the onset of AD-induced global glucose metabolism disorders in AD mice. Hyperglycemia and its accompanying metabolic disorders including energy metabolism down-regulation and oxidative stress were observed in the serum of AD mice. Meanwhile, global disturbance of branched-chain amino acid (BCAA) metabolism was detected, and the change of BCAA (leucine) was positively correlated to the alteration of glucose. Moreover, increased level of glucose and enhanced energy metabolism were observed in the pancreas of AD mice. The results suggest that the diabetes-promoting effects accompanying the progress of AD are achieved by down-regulating the global utilization of glucose and interfering with the metabolic function of pancreas. Since T2D is a risk factor for the pathogenesis of AD, our findings suggest that targeting the glucose metabolism dysfunctions might serve as a supplementary therapeutic strategy for Alzheimer’s disease.

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  1. 1.

    Kim B, Feldman EL. Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome. Exp Mol Med. 2015;47:e149.

  2. 2.

    Neth BJ, Craft S. Insulin resistance and Alzheimer’s disease: bioenergetic linkages. Front Aging Neurosci. 2017;9:345.

  3. 3.

    Waither G, Obert P, Dutheil F, Chapier R, Lesourd B, Naughton G, et al. Metabolic syndrome individuals with and without type 2 diabetes mellitus present generalized vascular dysfunction cross-sectional study. Arter Throm Vas. 2015;35:1022–U318.

  4. 4.

    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. 2014;5:161.

  5. 5.

    Kuljis RO, Salkovic-Petrisic M. Dementia, diabetes, Alzheimer’s disease, and insulin resistance in the brain: progress, dilemmas, new opportunities, and a hypothesis to tackle intersecting epidemics. J Alzheimers Dis. 2011;25:29–41.

  6. 6.

    de Nazareth AM. Type 2 diabetes mellitus in the pathophysiology of Alzheimer’s disease. Dement Neuropsychol. 2017;11:105–13.

  7. 7.

    Wegiel J, Wisniewski HM, Muzylak M, Tarnawski M, Badmajew E, Nowakowski J, et al. Fibrillar amyloid-beta production, accumulation, and recycling in transgenic mice pancreatic acinar cells and macrophages. Amyloid. 2000;7:95–104.

  8. 8.

    Figueroa DJ, Shi XP, Gardell SJ, Austin CP. Abetapp secretases are co-expressed with Abetapp in the pancreatic islets. J Alzheimers Dis. 2001;3:393–96.

  9. 9.

    Lu Z, Xie J, Yan R, Yu Z, Sun Z, Yu F, et al. A pilot study of pancreatic islet amyloid PET imaging with [18F]FDDNP. Nucl Med Commun. 2018;39:659–64.

  10. 10.

    Kurochkin IV, Guarnera E, Berezovsky IN. Insulin-degrading enzyme in the fight against Alzheimer’s disease. Trends Pharm Sci. 2018;39:49–58.

  11. 11.

    Kimura N. Diabetes mellitus induces Alzheimer’s disease pathology: histopathological evidence from animal models. Int J Mol Sci. 2016;17:503.

  12. 12.

    Bharadwaj P, Wijesekara N, Liyanapathirana M, Newsholme P, Ittner L, Fraser P, et al. The link between type 2 diabetes and neurodegeneration: roles for amyloid-beta, amylin, and tau proteins. J Alzheimers Dis. 2017;59:421–32.

  13. 13.

    Ahmed S, Mahmood Z, Zahid S. Linking insulin with Alzheimer’s disease: emergence as type III diabetes. Neurol Sci. 2015;36:1763–69.

  14. 14.

    Bosco D, Fava A, Plastino M, Montalcini T, Pujia A. Possible implications of insulin resistance and glucose metabolism in Alzheimer’s disease pathogenesis. J Cell Mol Med. 2011;15:1807–21.

  15. 15.

    Morris JK, Piccolo BD, Shankar K, Thyfault JP, Adams SH. The serum metabolomics signature of type 2 diabetes is obscured in Alzheimer’s disease. Am J Physiol Endocrinol Metab. 2018;314:E584–96.

  16. 16.

    Zhong F, Liu X, Zhou Q, Hao X, Lu Y, Guo S, et al. 1H NMR spectroscopy analysis of metabolites in the kidneys provides new insight into pathophysiological mechanisms: applications for treatment with Cordyceps sinensis. Nephrol Dial Transpl. 2012;27:556–65.

  17. 17.

    Liu X, Zhong F, Tang XL, Lian FL, Zhou Q, Guo SM, et al. Cordyceps sinensis protects against liver and heart injuries in a rat model of chronic kidney disease: a metabolomic analysis. Acta Pharm Sin. 2014;35:697–706.

  18. 18.

    Zhang T, Wang W, Huang J, Liu X, Zhang H, Zhang N. Metabolomic investigation of regional brain tissue dysfunctions induced by global cerebral ischemia. BMC Neurosci. 2016;17:25.

  19. 19.

    Ma HF, Liu X, Wu Y, Zhang NX. The intervention effects of acupuncture on fatigue induced by exhaustive physical exercises: a metabolomics investigation. Evid Based Complement Altern Med. 2015;2015:508302.

  20. 20.

    Jolivalt CG, Lee CA, Beiswenger KK, Smith JL, Orlov M, Torrance MA, 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;86:3265–74.

  21. 21.

    Janson J, Laedtke T, Parisi JE, O’Brien P, Petersen RC, Butler PC. Increased risk of type 2 diabetes in Alzheimer disease. Diabetes. 2004;53:474–81.

  22. 22.

    Steen E, Terry BM, Rivera EJ, Cannon JL, Neely TR, Tavares R, et al. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer’s disease - is this type 3 diabetes? J Alzheimers Dis. 2005;7:63–80.

  23. 23.

    Talbot K, Wang HY, Kazi H, Han LY, Bakshi KP, Stucky A, et al. Demonstrated brain insulin resistance in Alzheimer’s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline. J Clin Invest. 2012;122:1316–38.

  24. 24.

    Takeda S, Sato N, Uchio-Yamada K, Sawada K, Kunieda T, Takeuchi D, et al. Diabetes-accelerated memory dysfunction via cerebrovascular inflammation and A beta deposition in an Alzheimer mouse model with diabetes. Proc Natl Acad Sci USA. 2010;107:7036–41.

  25. 25.

    Jimenez-Palomares M, Ramos-Rodriguez JJ, Lopez-Acosta JF, Pacheco-Herrero M, Lechuga-Sancho AM, Perdomo G, et al. Increased A beta production prompts the onset of glucose intolerance and insulin resistance. Am J Physiol Endocrinol Metab. 2012;302:E1373–80.

  26. 26.

    Wijesekara N, Ahrens R, Sabale M, Wu L, Ha K, Verdile G, et al. Amyloid-beta and islet amyloid pathologies link Alzheimer’s disease and type 2 diabetes in a transgenic model. FASEB J. 2017;31:5409–18.

  27. 27.

    Gebregiworgis T, Powers R. Application of NMR metabolomics to search for human disease biomarkers. Comb Chem High T Scr. 2012;15:595–610.

  28. 28.

    Zhang AH, Sun H, Qiu S, Wang XJ. NMR-based metabolomics coupled with pattern recognition methods in biomarker discovery and disease diagnosis. Magn Reson Chem. 2013;51:549–56.

  29. 29.

    Dudka I, Kossowska B, Senhadri H, Latajka R, Hajek J, Andrzejak R, et al. Metabonomic analysis of serum of workers occupationally exposed to arsenic, cadmium and lead for biomarker research: a preliminary study. Environ Int. 2014;68:71–81.

  30. 30.

    Koivisto H, Leinonen H, Puurula M, Hafez HS, Barrera GA, Stridh MH, et al. Chronic pyruvate supplementation increases exploratory activity and brain energy reserves in young and middle-aged mice. Front Aging Neurosci. 2016;8:41.

  31. 31.

    Han B, Wang JH, Geng Y, Shen L, Wang HL, Wang YY, et al. Chronic stress contributes to cognitive dysfunction and hippocampal metabolic abnormalities in APP/PS1 mice. Cell Physiol Biochem. 2017;41:1766–76.

  32. 32.

    Zhou Q, Zheng H, Chen JX, Li C, Du Y, Xia HH, et al. Metabolic fate of glucose in the brain of APP/PS1 transgenic mice at 10 months of age: a C-13 NMR metabolomic study. Metab Brain Dis. 2018;33:1661–68.

  33. 33.

    Podlesniy P, Figueiro-Silva J, Llado A, Antonell A, Sanchez-Valle R, Alcolea D, et al. Low cerebrospinal fluid concentration of mitochondrial DNA in preclinical Alzheimer disease. Ann Neurol. 2013;74:655–68.

  34. 34.

    Gonzalez-Dominguez R, Garcia-Barrera T, Vitorica J, Gomez-Ariza JL. Application of metabolomics based on direct mass spectrometry analysis for the elucidation of altered metabolic pathways in serum from the APP/PS1 transgenic model of Alzheimer’s disease. J Pharm Biomed. 2015;107:378–85.

  35. 35.

    Gao HL, Zhang AH, Yu JB, Sun H, Kong L, Wang XQ, et al. High-throughput lipidomics characterize key lipid molecules as potential therapeutic targets of Kaixinsan protects against Alzheimer’s disease in APP/PS1 transgenic mice. J Chromatogr B. 2018;1092:286–95.

  36. 36.

    Yang X, Chen DL, Yang J, Liu T, Hu GY, Liang HL, et al. Effects of oligosaccharides from morinda officinalis on gut microbiota and metabolome of APP/PS1 transgenic mice. Front Neurol. 2018;9:412.

  37. 37.

    Woodhouse A, Fernandez-Martos CM, Atkinson RAK, Hanson KA, Collins JM, O’Mara AR, et al. Repeat propofol anesthesia does not exacerbate plaque deposition or synapse loss in APP/PS1 Alzheimer’s disease mice. BMC Anesth. 2018;18:47.

  38. 38.

    Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, et al. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2004;13:159–70.

  39. 39.

    Kamphuis W, Mamber C, Moeton M, Kooijman L, Sluijs JA, Jansen AHP, et al. GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS ONE. 2012;7:e42823.

  40. 40.

    Jackson RJ, Rudinskiy N, Herrmann AG, Croft S, Kim JM, Petrova V, et al. Human tau increases amyloid beta plaque size but not amyloid beta-mediated synapse loss in a novel mouse model of Alzheimer’s disease. Eur J Neurosci. 2016;44:3056–66.

  41. 41.

    Lee YH, Hsu HC, Kao PC, Shiao YJ, Yeh SHH, Shie FS, et al. Augmented insulin and leptin resistance of high fat diet-fed APPswe/PS1dE9 transgenic mice exacerbate obesity and glycemic dysregulation. Int J Mol Sci. 2018;19:2333.

  42. 42.

    Leahy JL, Bonnerweir S, Weir GC. Beta-cell dysfunction induced by chronic hyperglycemia - current ideas on mechanism of impaired glucose-induced insulin-secretion. Diabetes Care. 1992;15:442–55.

  43. 43.

    Daulatzai MA. Cerebral hypoperfusion and glucose hypometabolism: key pathophysiological modulators promote neurodegeneration, cognitive impairment, and Alzheimer’s disease. J Neurosci Res. 2017;95:943–72.

  44. 44.

    Ferreira IL, Resende R, Ferreiro E, Rego AC, Pereira CF. Multiple defects in energy metabolism in Alzheimer’s disease. Curr Drug Targets. 2010;11:1193–206.

  45. 45.

    Mosconi L, Berti V, Guyara-Quinn C, McHugh P, Petrongolo G, Osorio RS, et al. Perimenopause and emergence of an Alzheimer’s bioenergetic phenotype in brain and periphery. PLoS ONE. 2017;12:e0185926.

  46. 46.

    Das J, Ghosh J, Manna P, Sil PC. Taurine protects acetaminophen-induced oxidative damage in mice kidney through APAP urinary excretion and CYP2E1 inactivation. Toxicology. 2010;269:24–34.

  47. 47.

    Das J, Ghosh J, Manna P, Sil PC. Taurine suppresses doxorubicin-triggered oxidative stress and cardiac apoptosis in rat via up-regulation of PI3-K/Akt and inhibition of p53, p38-JNK. Biochem Pharm. 2011;81:891–909.

  48. 48.

    Chang CY, Shen CY, Kang CK, Sher YP, Sheu WHH, Chang CC, et al. Taurine protects HK-2 cells from oxidized LDL-induced cytotoxicity via the ROS-mediated mitochondrial and p53-related apoptotic pathways. Toxicol Appl Pharm. 2014;279:351–63.

  49. 49.

    Yardim-Akaydin S, Sepici A, Ozkan Y, Simsek B, Sepici V. Evaluation of allantoin levels as a new marker of oxidative stress in Behcet’s disease. Scand J Rheuma. 2006;35:61–64.

  50. 50.

    Li T, Zhang Z, Kolwicz SC, Abell L, Roe ND, Kim M, et al. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury. Cell Metab. 2017;25:374–85.

  51. 51.

    Newgard CB, An J, Bain JR, Muehlbauer MJ, Stevens RD, Lien LF, et al. A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance. Cell Metab. 2009;9:311–26.

  52. 52.

    Ruiz HH, Chi T, Shin AC, Lindtner C, Hsieh W, Ehrlich M, et al. Increased susceptibility to metabolic dysregulation in a mouse model of Alzheimer’s disease is associated with impaired hypothalamic insulin signaling and elevated BCAA levels. Alzheimers Dement. 2016;12:851–61.

  53. 53.

    Knight EM, Ruiz HH, Kim SH, Harte JC, Hsieh W, Glabe C, et al. Unexpected partial correction of metabolic and behavioral phenotypes of Alzheimer’s APP/PSEN1 mice by gene targeting of diabetes/Alzheimer’s-related Sorcs1. Acta Neuropathol Commun. 2016;4:16.

  54. 54.

    Wijesekara N, Goncalves RA, De Felice FG, Fraser PE. Impaired peripheral glucose homeostasis and Alzheimer’s disease. Neuropharmacology. 2018;136:172–81.

  55. 55.

    Yoshinari O, Igarashi K. Anti-diabetic effect of trigonelline and nicotinic acid, on KK-A(y) mice. Curr Med Chem. 2010;17:2196–202.

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This work was financially supported by the National Natural Science Foundation of China (Grant no. 21778061) and the National Science & Technology Major Project “Key New Drug Creation and Manufacturing Program” of China (Grant no. 2018ZX09711002).

Author information

XL, WW, HYZ and NXZ designed the study, XL, HYZ and NXZ wrote the manuscript, and XL, WW and HLC performed the experiments.

Correspondence to Hai-yan Zhang or Nai-xia Zhang.

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  • Alzheimer’s disease
  • type 2 diabetes
  • APP/PS1 transgenic mice
  • metabolomics
  • NMR
  • glucose metabolism dysfunctions