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Alterations in Cerebral Cortical Glucose and Glutamine Metabolism Precedes Amyloid Plaques in the APPswe/PSEN1dE9 Mouse Model of Alzheimer’s Disease

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Abstract

Alterations in brain energy metabolism have been suggested to be of fundamental importance for the development of Alzheimer’s disease (AD). However, specific changes in brain energetics in the early stages of AD are poorly known. The aim of this study was to investigate cerebral energy metabolism in the APPswe/PSEN1dE9 mouse prior to amyloid plaque formation. Acutely isolated cerebral cortical and hippocampal slices of 3-month-old APPswe/PSEN1dE9 and wild-type control mice were incubated in media containing [U-13C]glucose, [1,2-13C]acetate or [U-13C]glutamine, and tissue extracts were analyzed by mass spectrometry. The ATP synthesis rate of isolated whole-brain mitochondria was assessed by an on-line luciferin-luciferase assay. Significantly increased 13C labeling of intracellular lactate and alanine and decreased tricarboxylic acid (TCA) cycle activity were observed from cerebral cortical slices of APPswe/PSEN1dE9 mice incubated in media containing [U-13C]glucose. No changes in glial [1,2-13C]acetate metabolism were observed. Cerebral cortical slices from APPswe/PSEN1dE9 mice exhibited a reduced capacity for uptake and oxidative metabolism of glutamine. Furthermore, the ATP synthesis rate tended to be decreased in isolated whole-brain mitochondria of APPswe/PSEN1dE9 mice. Thus, several cerebral metabolic changes are evident in the APPswe/PSEN1dE9 mouse prior to amyloid plaque deposition, including altered glucose metabolism, hampered glutamine processing and mitochondrial dysfunctions.

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Abbreviations

ACSF:

Artificial cerebrospinal fluid

AD:

Alzheimer’s disease

GS:

Glutamine synthetase

M:

Molecular ion

MCL:

Molecular carbon labeling

PAG:

Phosphate-activated glutaminase

PDH:

Pyruvate dehydrogenase

TG:

Transgene

References

  1. De Strooper B, Karran E (2016) The Cellular Phase of Alzheimer’s Disease. Cell 164(4):603–615. doi:10.1016/j.cell.2015.12.056

    Article  PubMed  Google Scholar 

  2. Gibson GE, Shi Q (2010) A mitocentric view of Alzheimer’s disease suggests multi-faceted treatments. J Alzheimers Dis 20(Suppl 2):S591–S607. doi:10.3233/jad-2010-100336

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mosconi L, Pupi A, De Leon MJ (2008) Brain glucose hypometabolism and oxidative stress in preclinical Alzheimer’s disease. Ann N Y Acad Sci 1147:180–195. doi:10.1196/annals.1427.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Blass JP, Sheu RK, Gibson GE (2000) Inherent abnormalities in energy metabolism in Alzheimer disease. Interaction with cerebrovascular compromise. Ann N Y Acad Sci 903:204–221

    Article  CAS  PubMed  Google Scholar 

  5. Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR (2004) 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 13(2):159–170. doi:10.1093/hmg/ddh019

    Article  CAS  PubMed  Google Scholar 

  6. Garcia-Alloza M, Robbins EM, Zhang-Nunes SX, Purcell SM, Betensky RA, Raju S, Prada C, Greenberg SM, Bacskai BJ, Frosch MP (2006) Characterization of amyloid deposition in the APPswe/PS1dE9 mouse model of Alzheimer disease. Neurobiol Dis 24(3):516–524. doi:10.1016/j.nbd.2006.08.017

    Article  CAS  PubMed  Google Scholar 

  7. Lalonde R, Kim HD, Maxwell JA, Fukuchi K (2005) Exploratory activity and spatial learning in 12-month-old APP(695)SWE/co + PS1/DeltaE9 mice with amyloid plaques. Neurosci Lett 390(2):87–92. doi:10.1016/j.neulet.2005.08.028

    Article  CAS  PubMed  Google Scholar 

  8. Savonenko A, Xu GM, Melnikova T, Morton JL, Gonzales V, Wong MP, Price DL, Tang F, Markowska AL, Borchelt DR (2005) Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 18(3):602–617. doi:10.1016/j.nbd.2004.10.022

    Article  CAS  PubMed  Google Scholar 

  9. Minkeviciene R, Ihalainen J, Malm T, Matilainen O, Keksa-Goldsteine V, Goldsteins G, Iivonen H, Leguit N, Glennon J, Koistinaho J, Banerjee P, Tanila H (2008) Age-related decrease in stimulated glutamate release and vesicular glutamate transporters in APP/PS1 transgenic and wild-type mice. J Neurochem 105(3):584–594. doi:10.1111/j.1471-4159.2007.05147.x

    Article  CAS  PubMed  Google Scholar 

  10. Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fulop L, Penke B, Zilberter Y, Harkany T, Pitkanen A, Tanila H (2009) Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy. J Neurosci 29(11):3453–3462. doi:10.1523/jneurosci.5215-08.2009

    Article  CAS  PubMed  Google Scholar 

  11. Bak LK, Schousboe A, Waagepetersen HS (2006) The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 98(3):641–653. doi:10.1111/j.1471-4159.2006.03913.x

    Article  CAS  PubMed  Google Scholar 

  12. Blass JP (2001) Brain metabolism and brain disease: is metabolic deficiency the proximate cause of Alzheimer dementia? J Neurosci Res 66(5):851–856

    Article  CAS  PubMed  Google Scholar 

  13. Moreira PI, Carvalho C, Zhu X, Smith MA, Perry G (2010) Mitochondrial dysfunction is a trigger of Alzheimer’s disease pathophysiology. Biochim Biophys Acta 1802(1):2–10. doi:10.1016/j.bbadis.2009.10.006

    Article  CAS  PubMed  Google Scholar 

  14. Walls AB, Bak LK, Sonnewald U, Schousboe A, Waagepetersen HS (2014) Metabolic Mapping of Astrocytes and Neurons in Culture Using Stable Isotopes and Gas Chromatography-Mass Spectrometry (GC-MS). In: Hirrlinger J, Waagepetersen HS (eds) Brain Enegy Metabolism, vol 90. Humana Press, New York

    Google Scholar 

  15. Sonnewald U, Westergaard N, Schousboe A, Svendsen JS, Unsgard G, Petersen SB (1993) Direct demonstration by [13C]NMR spectroscopy that glutamine from astrocytes is a precursor for GABA synthesis in neurons. Neurochem Int 22(1):19–29

    Article  CAS  PubMed  Google Scholar 

  16. Amaral AI, Hadera MG, Tavares JM, Kotter MR, Sonnewald U (2016) Characterization of glucose-related metabolic pathways in differentiated rat oligodendrocyte lineage cells. Glia 64(1):21–34. doi:10.1002/glia.22900

    Article  PubMed  Google Scholar 

  17. Vaishnavi SN, Vlassenko AG, Rundle MM, Snyder AZ, Mintun MA, Raichle ME (2010) Regional aerobic glycolysis in the human brain. Proc Natl Acad Sci USA 107(41):17757–17762. doi:10.1073/pnas.1010459107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Vlassenko AG, Vaishnavi SN, Couture L, Sacco D, Shannon BJ, Mach RH, Morris JC, Raichle ME, Mintun MA (2010) Spatial correlation between brain aerobic glycolysis and amyloid-beta (Abeta) deposition. Proc Natl Acad Sci USA 107(41):17763–17767. doi:10.1073/pnas.1010461107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Harris RA, Tindale L, Lone A, Singh O, Macauley SL, Stanley M, Holtzman DM, Bartha R, Cumming RC (2016) Aerobic Glycolysis in the Frontal Cortex Correlates with Memory Performance in Wild-Type Mice But Not the APP/PS1 Mouse Model of Cerebral Amyloidosis. J Neurosci 36(6):1871–1878. doi:10.1523/jneurosci.3131-15.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Nilsen LH, Witter MP, Sonnewald U (2014) Neuronal and astrocytic metabolism in a transgenic rat model of Alzheimer’s disease. J Cereb Blood Flow Metab 34(5):906–914. doi:10.1038/jcbfm.2014.37

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lin AP, Shic F, Enriquez C, Ross BD (2003) Reduced glutamate neurotransmission in patients with Alzheimer’s disease—an in vivo (13)C magnetic resonance spectroscopy study. MAGMA 16(1):29–42. doi:10.1007/s10334-003-0004-x

    Article  CAS  PubMed  Google Scholar 

  22. Herrero-Mendez A, Almeida A, Fernandez E, Maestre C, Moncada S, Bolanos JP (2009) The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC/C-Cdh1. Nat Cell Biol 11(6):747–752. doi:10.1038/ncb1881

    Article  CAS  PubMed  Google Scholar 

  23. Yao J, Irwin RW, Zhao L, Nilsen J, Hamilton RT, Brinton RD (2009) Mitochondrial bioenergetic deficit precedes Alzheimer’s pathology in female mouse model of Alzheimer’s disease. Proc Natl Acad Sci USA 106(34):14670–14675. doi:10.1073/pnas.0903563106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kamphuis W, Orre M, Kooijman L, Dahmen M, Hol EM (2012) Differential cell proliferation in the cortex of the APPswePS1dE9 Alzheimer’s disease mouse model. Glia 60(4):615–629. doi:10.1002/glia.22295

    Article  PubMed  Google Scholar 

  25. Steele ML, Robinson SR (2012) Reactive astrocytes give neurons less support: implications for Alzheimer’s disease. Neurobiol Aging 33(2):423.e421-413. doi:10.1016/j.neurobiolaging.2010.09.018

    Article  Google Scholar 

  26. Ordonez-Gutierrez L, Anton M, Wandosell F (2015) Peripheral amyloid levels present gender differences associated with aging in AbetaPP/PS1 mice. J Alzheimers Dis 44(4):1063–1068. doi:10.3233/jad-141158

    CAS  PubMed  Google Scholar 

  27. Sailasuta N, Harris K, Tran T, Ross B (2011) Minimally invasive biomarker confirms glial activation present in Alzheimer’s disease: a preliminary study. Neuropsychiatr Dis Treat 7:495–499. doi:10.2147/ndt.s23721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Walton HS, Dodd PR (2007) Glutamate-glutamine cycling in Alzheimer’s disease. Neurochem Int 50(7–8):1052–1066. doi:10.1016/j.neuint.2006.10.007

    Article  CAS  PubMed  Google Scholar 

  29. Robinson SR (2000) Neuronal expression of glutamine synthetase in Alzheimer’s disease indicates a profound impairment of metabolic interactions with astrocytes. Neurochem Int 36(4–5):471–482

    Article  CAS  PubMed  Google Scholar 

  30. Kulijewicz-Nawrot M, Sykova E, Chvatal A, Verkhratsky A, Rodriguez JJ (2013) Astrocytes and glutamate homoeostasis in Alzheimer’s disease: a decrease in glutamine synthetase, but not in glutamate transporter-1, in the prefrontal cortex. ASN Neuro 5(4):273–282. doi:10.1042/an20130017

    Article  CAS  PubMed  Google Scholar 

  31. McGeer EG, McGeer PL, Akiyama H, Harrop R (1989) Cortical glutaminase, beta-glucuronidase and glucose utilization in Alzheimer’s disease. Can J Neurol Sci 16(4 Suppl):511–515

    Article  CAS  PubMed  Google Scholar 

  32. Burbaeva G, Boksha IS, Tereshkina EB, Savushkina OK, Prokhorova TA, Vorobyeva EA (2014) Glutamate and GABA-metabolizing enzymes in post-mortem cerebellum in Alzheimer’s disease: phosphate-activated glutaminase and glutamic acid decarboxylase. Cerebellum 13(5):607–615. doi:10.1007/s12311-014-0573-4

    Article  CAS  PubMed  Google Scholar 

  33. Akiyama H, McGeer PL, Itagaki S, McGeer EG, Kaneko T (1989) Loss of glutaminase-positive cortical neurons in Alzheimer’s disease. Neurochem Res 14(4):353–358

    Article  CAS  PubMed  Google Scholar 

  34. Bubber P, Haroutunian V, Fisch G, Blass JP, Gibson GE (2005) Mitochondrial abnormalities in Alzheimer brain: mechanistic implications. Ann Neurol 57(5):695–703. doi:10.1002/ana.20474

    Article  CAS  PubMed  Google Scholar 

  35. Hauptmann S, Scherping I, Drose S, Brandt U, Schulz KL, Jendrach M, Leuner K, Eckert A, Muller WE (2009) Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice. Neurobiol Aging 30(10):1574–1586. doi:10.1016/j.neurobiolaging.2007.12.005

    Article  CAS  PubMed  Google Scholar 

  36. Du H, Guo L, Yan S, Sosunov AA, McKhann GM, Yan SS (2010) Early deficits in synaptic mitochondria in an Alzheimer’s disease mouse model. Proc Natl Acad Sci USA 107(43):18670–18675. doi:10.1073/pnas.1006586107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Zhang C, Rissman RA, Feng J (2015) Characterization of ATP alternations in an Alzheimer’s disease transgenic mouse model. J Alzheimers Dis 44(2):375–378. doi:10.3233/jad-141890

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Pedros I, Petrov D, Allgaier M, Sureda F, Barroso E, Beas-Zarate C, Auladell C, Pallas M, Vazquez-Carrera M, Casadesus G, Folch J, Camins A (2014) Early alterations in energy metabolism in the hippocampus of APPswe/PS1dE9 mouse model of Alzheimer’s disease. Biochim Biophys Acta 1842(9):1556–1566. doi:10.1016/j.bbadis.2014.05.025

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The competent laboratory assistance of Catia Andersen is cordially acknowledged. The Lundbeck Foundation and the Scholarship of Peter & Emma Thomsen are acknowledged for their financial support to JVA.

Author contributions

All authors designed the experiments. JVA, SKC, BIA, and JDN performed the experiments and analyzed the data. JVA and HSW wrote the article. All authors have provided constructive input and have approved the final manuscript.

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Authors and Affiliations

  1. Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Jens V. Andersen, Sofie K. Christensen, Blanca I. Aldana, Jakob D. Nissen & Helle S. Waagepetersen

  2. A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland

    Heikki Tanila

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  1. Jens V. Andersen
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Correspondence to Helle S. Waagepetersen.

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Special Issue: In honour of Ursula Sonnewald.

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Andersen, J.V., Christensen, S.K., Aldana, B.I. et al. Alterations in Cerebral Cortical Glucose and Glutamine Metabolism Precedes Amyloid Plaques in the APPswe/PSEN1dE9 Mouse Model of Alzheimer’s Disease. Neurochem Res 42, 1589–1598 (2017). https://doi.org/10.1007/s11064-016-2070-2

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  • DOI: https://doi.org/10.1007/s11064-016-2070-2

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