Advertisement

Metabolic Brain Disease

, Volume 33, Issue 5, pp 1563–1571 | Cite as

The locus coeruleus neurotoxin, DSP4, and/or a high sugar diet induce behavioral and biochemical alterations in wild-type mice consistent with Alzheimers related pathology

  • Pooja Choudhary
  • Anthony G. Pacholko
  • Josh Palaschuk
  • Lane K. Bekar
Original Article

Abstract

Alzheimer’s disease (AD) is the sixth leading cause of death in the United States where it is estimated that one in three seniors dies with AD or another dementia. Are modern lifestyle habits a contributing factor? Increased carbohydrate (sugar) consumption, stress and disruption of sleep patterns are quickly becoming the norm rather than the exception. Interestingly, seven months on a non-invasive high sucrose diet (20% sucrose in drinking water) has been shown to induce behavioral, metabolic and pathological changes consistent with AD in wild-type mice. As chronic stress and depression are associated with loss of locus coeruleus (LC) noradrenergic neurons and projections (source of anti-inflammatory and trophic factor control), we assessed the ability for a selective LC neurotoxin (DSP4) to accelerate and aggravate a high-sucrose mediated AD-related phenotype in wild-type mice. Male C57/Bl6 mice were divided into four groups: 1) saline injected, 2) DSP4 injected, 3) high sucrose drinking water (20%) or 4) DSP4 injected and high sucrose drinking water. We demonstrate that high sucrose consumption and DSP4 treatment promote an early-stage AD-related phenotype after only 3–4 months, as evidenced by elevated fecal corticosterone, increased despair, spatial memory deficits, increased AChE activity, elevated NO production, decreased pGSK3β and increased pTau. Combined treatment appears to accelerate and aggravate pathological processes consistent with Alzheimer disease and dementia. Developing a simple model in wild-type mice will highlight environmental and lifestyle factors that need to be addressed to slow, prevent or even reverse the rising trend in dementia patient numbers and cost.

Keywords

Insulin resistant brain state GSK3beta Phosphorylated Tau Locus coeruleus 

Notes

Acknowledgements

This work was supported by the Saskatchewan Health Research Foundation (SHRF grant number 3075.

Compliance with ethical standards

Disclosures

None of the authors have any conflicts, financial or otherwise, to disclose. All authors approved the final manuscript.

References

  1. Alzheimer Association (2016) 2016 Alzheimer's disease facts and figures. Alzheimers Dement 12:459–509CrossRefGoogle Scholar
  2. Bekar LK, Wei HS, Nedergaard M (2012) The locus coeruleus-norepinephrine network optimizes coupling of cerebral blood volume with oxygen demand. J Cereb Blood Flow Metab 32:2135–2145.  https://doi.org/10.1038/jcbfm.2012.115 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Beurel E, Grieco SF, Jope RS (2015) Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. Pharmacol Ther 148:114–131.  https://doi.org/10.1016/j.pharmthera.2014.11.016 CrossRefPubMedGoogle Scholar
  4. Cao D, Lu H, Lewis TL, Li L (2007) Intake of sucrose-sweetened water induces insulin resistance and exacerbates memory deficits and amyloidosis in a transgenic mouse model of Alzheimer disease. J Biol Chem 282:36275–36282.  https://doi.org/10.1074/jbc.M703561200 CrossRefPubMedGoogle Scholar
  5. Carvalho C, Cardoso S, Correia SC et al (2012) Metabolic alterations induced by sucrose intake and Alzheimer's disease promote similar brain mitochondrial abnormalities. Diabetes 61:1234–1242.  https://doi.org/10.2337/db11-1186 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Carvalho C, Machado N, Mota PC et al (2013) Type 2 diabetic and Alzheimer's disease mice present similar behavioral, cognitive, and vascular anomalies. J Alzheimers Dis 35:623–635.  https://doi.org/10.3233/JAD-130005 CrossRefPubMedGoogle Scholar
  7. Chen TC, Benjamin DI, Kuo T et al (2017) The glucocorticoid-Angptl4-ceramide axis induces insulin resistance through PP2A and PKCzeta. Sci Signal 10.  https://doi.org/10.1126/scisignal.aai7905 CrossRefPubMedGoogle Scholar
  8. Chitturi S, Abeygunasekera S, Farrell GC et al (2002) NASH and insulin resistance: Insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology 35:373–379.  https://doi.org/10.1053/jhep.2002.30692 CrossRefPubMedGoogle Scholar
  9. Counts SE, Mufson EJ (2010) Noradrenaline activation of neurotrophic pathways protects against neuronal amyloid toxicity. J Neurochem 113:649–660.  https://doi.org/10.1111/j.1471-4159.2010.06622.x CrossRefPubMedPubMedCentralGoogle Scholar
  10. de la Monte SM (2012) Triangulated mal-signaling in Alzheimer's disease: roles of neurotoxic ceramides, ER stress, and insulin resistance reviewed. J Alzheimers Dis 30(Suppl 2):S231–S249.  https://doi.org/10.3233/jad-2012-111727 CrossRefPubMedPubMedCentralGoogle Scholar
  11. de la Monte SM, Tong M, Nguyen V, Setshedi M, Longato L, Wands JR (2010) Ceramide-mediated insulin resistance and impairment of cognitive-motor functions. J Alzheimers Dis 21:967–984.  https://doi.org/10.3233/jad-2010-091726 CrossRefPubMedPubMedCentralGoogle Scholar
  12. de Mello VD, Lankinen M, Schwab U et al (2009) Link between plasma ceramides, inflammation and insulin resistance: association with serum IL-6 concentration in patients with coronary heart disease. Diabetologia 52:2612–2615.  https://doi.org/10.1007/s00125-009-1482-9 CrossRefPubMedGoogle Scholar
  13. Debeir T, Marien M, Ferrario J, Rizk P, Prigent A, Colpaert F, Raisman-Vozari R (2004) In vivo upregulation of endogenous NGF in the rat brain by the alpha2-adrenoreceptor antagonist dexefaroxan: potential role in the protection of the basalocortical cholinergic system during neurodegeneration. Exp Neurol 190:384–395CrossRefPubMedGoogle Scholar
  14. Dudley MW, Howard BD, Cho AK (1990) The interaction of the beta-haloethyl benzylamines, xylamine, and DSP-4 with catecholaminergic neurons. Annu Rev Pharmacol Toxicol 30:387–403CrossRefPubMedGoogle Scholar
  15. Feinstein DL, Heneka MT, Gavrilyuk V, Dello Russo C, Weinberg G, Galea E (2002) Noradrenergic regulation of inflammatory gene expression in brain. Neurochem Int 41:357–365CrossRefPubMedGoogle Scholar
  16. Fritschy JM, Grzanna R (1991) Experimentally-induced neuron loss in the locus coeruleus of adult rats. Exp Neurol 111:123–127CrossRefPubMedGoogle Scholar
  17. Fritschy JM, Geffard M, Grzanna R (1990) The response of noradrenergic axons to systemically administered DSP-4 in the rat: an immunohistochemical study using antibodies to noradrenaline and dopamine-beta-hydroxylase. J Chem Neuroanat 3:309–321PubMedGoogle Scholar
  18. Gavrilyuk V, Dello Russo C, Heneka MT, Pelligrino D, Weinberg G, Feinstein DL (2002) Norepinephrine increases I kappa B alpha expression in astrocytes. J Biol Chem 277:29662–29668CrossRefPubMedGoogle Scholar
  19. Guix FX, Wahle T, Vennekens K et al (2012) Modification of γ-secretase by nitrosative stress links neuronal ageing to sporadic Alzheimer's disease. EMBO Mol Med 4:660–673.  https://doi.org/10.1002/emmm.201200243 CrossRefPubMedPubMedCentralGoogle Scholar
  20. Harik SI, LaManna JC, Light AI, Rosenthal M (1979) Cerebral norepinephrine: influence on cortical oxidative metabolism in situ. Science 206:69–71CrossRefPubMedGoogle Scholar
  21. Harper JM, Austad SN (2000) Fecal glucocorticoids: a noninvasive method of measuring adrenal activity in wild and captive rodents. Physiol Biochem Zool 73:12–22.  https://doi.org/10.1086/316721 CrossRefPubMedGoogle Scholar
  22. Hauser J, Sontag TA, Tucha O, Lange KW (2012) The effects of the neurotoxin DSP4 on spatial learning and memory in Wistar rats. Atten Defic Hyperact Disord 4:93–99.  https://doi.org/10.1007/s12402-012-0076-4 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Heneka MT, Galea E, Gavriluyk V et al (2002) Noradrenergic depletion potentiates beta -amyloid-induced cortical inflammation: implications for Alzheimer's disease. J Neurosci 22:2434–2442CrossRefPubMedGoogle Scholar
  24. Heneka MT, Ramanathan M, Jacobs AH et al (2006) Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci 26:1343–1354CrossRefPubMedGoogle Scholar
  25. Hernandez F, Lucas JJ, Avila J (2013) GSK3 and tau: two convergence points in Alzheimer's disease. J Alzheimers Dis 33(Suppl 1):S141–S144.  https://doi.org/10.3233/JAD-2012-129025 CrossRefPubMedGoogle Scholar
  26. Hooper C, Killick R, Lovestone S (2008) The GSK3 hypothesis of Alzheimer's disease. J Neurochem 104:1433–1439.  https://doi.org/10.1111/j.1471-4159.2007.05194.x CrossRefPubMedPubMedCentralGoogle Scholar
  27. Jardanhazi-Kurutz D, Kummer MP, Terwel D, Vogel K, Dyrks T, Thiele A, Heneka MT (2010) Induced LC degeneration in APP/PS1 transgenic mice accelerates early cerebral amyloidosis and cognitive deficits. Neurochem Int 57:375–382.  https://doi.org/10.1016/j.neuint.2010.02.001 CrossRefPubMedGoogle Scholar
  28. Kalinin S, Gavrilyuk V, Polak PE, Vasser R, Zhao J, Heneka MT, Feinstein DL (2007) Noradrenaline deficiency in brain increases beta-amyloid plaque burden in an animal model of Alzheimer's disease. Neurobiol Aging 28:1206–1214.  https://doi.org/10.1016/j.neurobiolaging.2006.06.003 CrossRefPubMedGoogle Scholar
  29. Krishna M (2013) Role of special stains in diagnostic liver pathology. Clin Liver Dis 2.  https://doi.org/10.1002/cld.148 CrossRefGoogle Scholar
  30. Kwak YD, Wang R, Li JJ, Zhang YW, Xu H, Liao FF (2011) Differential regulation of BACE1 expression by oxidative and nitrosative signals. Mol Neurodegener 6:17.  https://doi.org/10.1186/1750-1326-6-17 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Lemos C, Rial D, Goncalves FQ et al (2016) High sucrose consumption induces memory impairment in rats associated with electrophysiological modifications but not with metabolic changes in the hippocampus. Neuroscience 315:196–205.  https://doi.org/10.1016/j.neuroscience.2015.12.018 CrossRefPubMedGoogle Scholar
  32. Lyn-Cook LE, Lawton M, Tong M et al (2009) Hepatic ceramide may mediate brain insulin resistance and neurodegeneration in type 2 diabetes and non-alcoholic steatohepatitis. J Alzheimers Dis 16:715–729.  https://doi.org/10.3233/JAD-2009-0984 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Marien MR, Colpaert FC, Rosenquist AC (2004) Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res Brain Res Rev 45:38–78CrossRefPubMedGoogle Scholar
  34. McIntosh LJ, Hong KE, Sapolsky RM (1998) Glucocorticoids may alter antioxidant enzyme capacity in the brain: baseline studies. Brain Res 791:209–214CrossRefPubMedGoogle Scholar
  35. Moreira PI (2013) High-sugar diets, type 2 diabetes and Alzheimer's disease. Curr Opin Clin Nutr Metab Care 16:440–445.  https://doi.org/10.1097/MCO.0b013e328361c7d1 CrossRefPubMedGoogle Scholar
  36. Osmanovic J, Plaschke K, Salkovic-Petrisic M, Grünblatt E, Riederer P, Hoyer S (2010) Chronic exogenous corticosterone administration generates an insulin-resistant brain state in rats. Stress 13:123–131.  https://doi.org/10.3109/10253890903080379 CrossRefPubMedGoogle Scholar
  37. Parr C, Mirzaei N, Christian M, Sastre M (2015) Activation of the Wnt/β-catenin pathway represses the transcription of the β-amyloid precursor protein cleaving enzyme (BACE1) via binding of T-cell factor-4 to BACE1 promoter. FASEB J 29:623–635.  https://doi.org/10.1096/fj.14-253211 CrossRefPubMedGoogle Scholar
  38. Peppiatt CM, Howarth C, Mobbs P, Attwell D (2006) Bidirectional control of CNS capillary diameter by pericytes. Nature 443:700–704CrossRefPubMedPubMedCentralGoogle Scholar
  39. Raichle ME, Hartman BK, Eichling JO, Sharpe LG (1975) Central noradrenergic regulation of cerebral blood flow and vascular permeability. Proc Natl Acad Sci U S A 72:3726–3730CrossRefPubMedPubMedCentralGoogle Scholar
  40. Salkovic-Petrisic M, Hoyer S (2007) Central insulin resistance as a trigger for sporadic Alzheimer-like pathology: an experimental approach. J Neural Transm Suppl:217–233Google Scholar
  41. Salkovic-Petrisic M, Osmanovic J, Grünblatt E, Riederer P, Hoyer S (2009) Modeling sporadic Alzheimer's disease: the insulin resistant brain state generates multiple long-term morphobiological abnormalities including hyperphosphorylated tau protein and amyloid-beta. J Alzheimers Dis 18:729–750.  https://doi.org/10.3233/JAD-2009-1184 CrossRefPubMedGoogle Scholar
  42. Scheiblich H, Schlutter A, Golenbock DT, Latz E, Martinez-Martinez P, Heneka MT (2017) Activation of the NLRP3 inflammasome in microglia: The role of ceramide. J Neurochem.  https://doi.org/10.1111/jnc.14225 CrossRefPubMedGoogle Scholar
  43. Seol GH, Ziburkus J, Huang S et al (2007) Neuromodulators control the polarity of spike-timing-dependent synaptic plasticity. Neuron 55:919–929CrossRefPubMedPubMedCentralGoogle Scholar
  44. Stranahan AM, Arumugam TV, Cutler RG, Lee K, Egan JM, Mattson MP (2008a) Diabetes impairs hippocampal function through glucocorticoid-mediated effects on new and mature neurons. Nat Neurosci 11:309–317.  https://doi.org/10.1038/nn2055 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Stranahan AM, Lee K, Pistell PJ et al (2008b) Accelerated cognitive aging in diabetic rats is prevented by lowering corticosterone levels. Neurobiol Learn Mem 90:479–483.  https://doi.org/10.1016/j.nlm.2008.05.005 CrossRefPubMedPubMedCentralGoogle Scholar
  46. Szot P, Franklin A, Miguelez C et al (2016) Depressive-like behavior observed with a minimal loss of locus coeruleus (LC) neurons following administration of 6-hydroxydopamine is associated with electrophysiological changes and reversed with precursors of norepinephrine. Neuropharmacology 101:76–86.  https://doi.org/10.1016/j.neuropharm.2015.09.003 CrossRefPubMedGoogle Scholar
  47. Tong M, de la Monte SM (2009) Mechanisms of ceramide-mediated neurodegeneration. J Alzheimers Dis 16:705–714.  https://doi.org/10.3233/JAD-2009-0983 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Wang ZJ, Zhang XQ, Cui XY et al (2015) Glucocorticoid receptors in the locus coeruleus mediate sleep disorders caused by repeated corticosterone treatment. Sci Rep 5:9442.  https://doi.org/10.1038/srep09442 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Zarow C, Lyness SA, Mortimer JA, Chui HC (2003) Neuronal loss is greater in the locus coeruleus than nucleus basalis and substantia nigra in Alzheimer and Parkinson diseases. Arch Neurol 60:337–341CrossRefPubMedGoogle Scholar
  50. Zhang J, Zhu Y, Zhan G et al (2014) Extended wakefulness: compromised metabolics in and degeneration of locus ceruleus neurons. J Neurosci 34:4418–4431.  https://doi.org/10.1523/JNEUROSCI.5025-12.2014 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Pharmacology, College of MedicineUniversity of SaskatchewanSaskatoonCanada

Personalised recommendations