Abstract
Alzheimer’s disease is associated with genetic risk factors, of which the apolipoprotein E (ApoE) is the most prevalent, and is affected by environmental factors that include education early in life and exposure to metals. The industrial and military use of depleted uranium (DU) resulted in an increase of its deposition in some areas and led to a possible environmental factor. The present study aims to ascertain the effects on the behaviour and the metabolism of cholesterol and acetylcholine of ApoE−/− mice exposed to enriched environment (EE) and exposed to DU (20 mg/L) for 14 weeks. Here we show that ApoE−/− mice were unaffected by the EE and their learning and memory were similar to those of the non-enriched ApoE−/− mice. ApoE−/− mice showed a significant decrease in total (−16 %) and free (−16 %) cholesterol in the entorhinal cortex in comparison to control wild-type mice. Whatever the housing conditions, the exposure to DU of ApoE−/− mice impaired working memory, but had no effect on anxiety-like behaviour, in comparison to control ApoE−/− mice. The exposure of ApoE−/− mice to DU also induced a trend toward higher total cholesterol content in the cerebral cortex (+15 %) compared to control ApoE−/− mice. In conclusion, these results demonstrate that enriched environment does not ameliorate neurobehaviour in ApoE−/− mice and that ApoE mutation induced specific effects on the brain cholesterol. These findings also suggested that DU exposure could modify the pathology in this ApoE model, with no influence of housing conditions.
Similar content being viewed by others
References
Abou-Donia MB, Goldstein LB, Jones KH et al (2001) Locomotor and sensorimotor performance deficit in rats following exposure to pyridostigmine bromide, DEET, and permethrin, alone and in combination. Toxicol Sci 60(2):305–314
Anderson R, Higgins GA (1997) Absence of central cholinergic deficits in ApoE knockout mice. Psychopharmacology 132(2):135–144
ATSDR (Agency for Toxic Substances and Disease Registry) (1999) Toxicological profile for uranium. US Public Health Service, Department of Health & Human Services, Atlanta
Bensoussan H, Grandcolas L, Dhieux-Lestaevel B et al (2009) Heavy metal uranium affects the brain cholinergic system in rat following sub-chronic and chronic exposure. Toxicology 261(1–2):59–67
Bleise A, Danesi PR, Burkart W (2003) Properties, use and health effects of depleted uranium (DU): a general overview. J Environ Radioact 64(2–3):93–112
Bernberg E, Andersson IJ, Gan LM, Naylor AS, Johansson ME, Bergström G (2008) Effects of social isolation and environmental enrichment on atherosclerosis in ApoE−/− mice. Stress 11(5):381–389
Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254
Briner W, Murray J (2005) Effects of short-term and long-term depleted uranium exposure on open-field behavior and brain lipid oxidation in rats. Neurotoxicol Teratol 27(1):135–144
Bronfman FC, Tesseur I, Hofker MH, Havekens LM, Van Leuven F (2000) No evidence for cholinergic problems in apolipoprotein E knockout and apolipoprotein E4 transgenic mice. Neuroscience 97(3):411–418
Bruel-Jungerman E, Laroche S, Rampon C (2005) New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. Eur J Neurosci 21(2):513–521
Bussy C, Lestaevel P, Dhieux B et al (2006) Chronic ingestion of uranyl nitrate perturbs acetylcholinesterase activity and monoamine metabolism in male rat brain. Neurotoxicology 27(2):245–252
Buttini M, Yu GQ, Shockley K et al (2002) Modulation of Alzheimer-like synaptic and cholinergic deficits in transgenic mice by human apolipoprotein E depends on isoform, aging, and overexpression of amyloid beta peptides but not on plaque formation. J Neurosci 22(24):10539–10548
Chapman S, Michaelson DM (1998) Specific neurochemical derangements of brain projecting neurons in apolipoprotein E-deficient mice. J Neurochem 70(2):708–714
Corder EH, Saunders AM, Strittmatter WJ et al (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 261(5123):921–923
Darnaudéry M, Dutriez I, Viltart O, Morley-Fletcher S, Maccari S (2004) Stress during gestation induces lasting effects on emotional reactivity of the dam rat. Behav Brain Res 153(1):211–216
Flaten TP (2001) Aluminium as a risk factor in Alzheimer's disease, with emphasis on drinking water. Brain Res Bull 55(2):187–196
Gerlai R (1996) Gene-targeting studies of mammalian behavior: is it the mutation or the background genotype? Trends Neurosci 19(5):177–181
Gordon I, Grauer E, Genis I, Sehayek E, Michaelson DM (1995) Memory deficits and cholinergic impairments in apolipoprotein E-deficient mice. Neurosci Lett 199(1):1–4
Guo Y, Zhang C, Du X, Nair U, Yoo TJ (2005) Morphological and functional alterations of the cochlea in apolipoprotein E gene deficient mice. Hear Res 208(1–2):54–67
Hayashi H (2011) Lipid metabolism and glial lipoproteins in the central nervous system. Biol Pharm Bull 34(4):453–461
Hock C, Drasch G, Golombowski S, Müller-Spahn F, Willershausen-Zönnchen B, Schwarz P, Hock U, Growdon JH, Nitsch RM (1998) Increased blood mercury levels in patients with Alzheimer's disease. J Neural Transm 105(1):59–68
Katzman R (1993) Education and the prevalence of dementia and Alzheimer's disease. Neurology 43(1):13–20
Kawas CH, Clark CM, Farlow MR, Knopman DS, Marson D, Morris JC, Thal LJ, Whitehouse PJ (1999) Clinical trials in Alzheimer disease: debate on the use of placebo controls. Alzheimer Dis Assoc Disord 13(3):124–129
Kim J, Basak JM, Holtzman DM (2009) The role of apolipoprotein E in Alzheimer's disease. Neuron 63(3):287–303
Kleifeld O, Diebler MF, Chapman S, Oron L, Michaelson DM (1998) The effects of apolipoprotein E deficiency on brain cholinergic neurons. Int J Dev Neurosci 16(7–8):755–762
Krzywkowski P, Ghribi O, Gagné J et al (1999) Cholinergic systems and long-term potentiation in memory-impaired apolipoprotein E-deficient mice. Neuroscience 92(4):1273–1286
Lemercier V, Millot X, Ansoborlo E et al (2003) Study of uranium transfer across the blood–brain barrier. Radiat Prot Dosimetry 105(1–4):243–245
Lestaevel P, Romero E, Dhieux B et al (2009) Different pattern of brain pro-/anti-oxidant activity between depleted and enriched uranium in chronically exposed rats. Toxicology 258(1):1–9
Lestaevel P, Bensoussan H, Racine R, Airault F, Gourmelon P, Souidi M (2011) Transcriptomic effects of depleted uranium on acetylcholine and cholesterol metabolisms in Alzheimer's disease model. C R Biol 334(2):85–90
Levi O, Jongen-Relo AL, Feldon J, Roses AD, Michaelson DM (2003) ApoE4 impairs hippocampal plasticity isoform-specifically and blocks the environmental stimulation of synaptogenesis and memory. Neurobiol Dis 13(3):273–282
Martyn CN, Barker DJ, Osmond C, Harris EC, Edwardson JA, Lacey RF (1989) Geographical relation between Alzheimer's disease and aluminum in drinking water. Lancet 1(8629):59–62
Masliah E, Mallory M, Ge N, Alford M, Veinbergs I, Roses AD (1995) Neurodegeneration in the central nervous system of apoE-deficient mice. Exp Neurol 136(2):107–122
McDiarmid MA, Hooper FJ, Squibb K et al (2002) Health effects and biological monitoring results of Gulf War veterans exposed to depleted uranium. Mil Med 167(2):123–124
McLachlan CS, Yi Xing SC (2005) Differences in anxiety-related behavior between apolipoprotein E-deficient C57BL/6 and wild type C57BL/6 mice. Physiol Res 54(6):701–704
Moceri VM, Kukull WA, Emanuel I, van Belle G, Larson EB (2000) Early-life risk factors and the development of Alzheimer's disease. Neurology 54(2):415–420
Moghadasian MH, McManus BM, Nguyen LB et al (2001) Pathophysiology of apolipoprotein E deficiency in mice: relevance to apo E-related disorders in humans. FASEB J 15(14):2623–2630
Muikku M, Heikkinen T, Puhakainen M, Rahola T, Salonen L (2007) Assessment of occupational exposure to uranium by indirect methods needs information on natural background variations. Radiat Prot Dosimetry 125(1–4):492–495
Oitzl MS, Mulder M, Lucassen PJ, Havekes LM, Grootendorst J, de Kloet ER (1997) Severe learning deficits in apolipoprotein E-knockout mice in a water maze task. Brain Res 752(1–2):189–196
Pellmar TC, Fuciarelli AF, Ejnik JW et al (1999a) Distribution of uranium in rats implanted with depleted uranium pellets. Toxicol Sci 49(1):29–39
Pellmar TC, Keyser DO, Emery C, Hogan JB (1999b) Electrophysiological changes in hippocampal slices isolated from rats embedded with depleted uranium fragments. Neurotoxicology 20(5):785–792
Poirier J, Davignon J, Bouthillier D, Kogan S, Bertrand P, Gauthier S (1993) Apolipoprotein E polymorphism and Alzheimer's disease. Lancet 342(8873):697–699
Poirier J (1994) Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci 17(12):525–530
Raber J, Wong D, Buttini M et al (1998) Isoform-specific effects of human apolipoprotein E on brain function revealed in ApoE knockout mice: increased susceptibility of females. Proc Natl Acad Sci USA 95(18):10914–10919
Racine R, Gueguen Y, Gourmelon P, Veyssiere G, Souidi M (2009) Modifications of the expression of genes involved in cerebral cholesterol metabolism in the rat following chronic ingestion of depleted uranium. J Mol Neurosci 38(2):159–165
Racine R, Grandcolas L, Grison S et al (2010) Cholesterol 7alpha-hydroxylase (CYP7A1) activity is modified after chronic ingestion of depleted uranium in the rat. J Steroid Biochem Mol Biol 120(1):60–66
Rampon C, Jiang CH, Dong H, Tang YP, Lockhart DJ, Schultz PG, Tsien JZ, Hu Y (2000) Effects of environmental enrichment on gene expression in the brain. Proc Natl Acad Sci U S A 97(23):12880–12884
Robertson J, Curley J, Kaye J, Quinn J, Pfankuch T, Raber J (2005) ApoE isoforms and measures of anxiety in probable AD patients and Apoe−/− mice. Neurobiol Aging 26(5):637–643
Rosenzweig MR (1966) Environmental complexity, cerebral change, and behavior. Am Psychol 21(4):321–332
Soininen H, Kosunen O, Helisalmi S et al (1995) A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein epsilon 4 allele. Neurosci Lett 187(2):79–82
Souidi M, Racine R, Grandcolas L, Grison S, Stefani J, Gourmelon P, Lestaevel P (2012) Influence of depleted uranium on hepatic cholesterol metabolism in apolipoprotein E-deficient mice. J Steroid Biochem Mol Biol 129(3–5):201–205
Van Praag H, Kempermann G, Gage FH (2000) Neural consequences of environmental enrichment. Nat Rev Neurosci 1(3):191–198
Zlokovic BV, Martel CL, Mackic JB, Matsubara E, Wisniewski T, McComb JG, Frangione B, Ghiso J (1994) Brain uptake of circulating apolipoproteins J and E complexed to Alzheimer’s amyloid beta. Biochem Biophys Res Commun 205(2):1431–1437
Acknowledgments
This work was part of the ENVIRHOM research program supported by the Institute for Radiological Protection and Nuclear Safety (IRSN). The authors thank Cédric Baudelin, Frédéric Voyer and Thierry Loiseau for the breeding, the care and the contamination of the ApoE−/− mice.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Lestaevel, P., Airault, F., Racine, R. et al. Influence of Environmental Enrichment and Depleted Uranium on Behaviour, Cholesterol and Acetylcholine in Apolipoprotein E-Deficient Mice. J Mol Neurosci 53, 469–479 (2014). https://doi.org/10.1007/s12031-013-0038-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-013-0038-0