Abstract
Mice deficient in acetylcholinesterase (AChE; EC3.1.1.7) exhibited significant phenotypical and biochemical changes when compared with wild-type littermates. They showed a delay of growth in weight and size, immature external ears, and persistent body tremor, and they circled when walking. The molecular mechanisms underlying these changes have not been investigated yet. Here, we studied the profiles of both the messenger RNA (mRNA) and protein expression in the brain of AChE-deficient mice using mRNA microarray, quantitative PCR, and two-dimensional difference gel electrophoresis (2D DIGE) coupled to protein identification with matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry. Analysis of gene expression profile was conducted by DAVID (http://david.abcc.ncifcrf.gov) and Ingenuity Pathway Analysis (IPA, http://www.ingenuity.com). Previous results implicated that there is a close relationship between lipid metabolisms which were associated with central nervous system development. Here, we demonstrated that the mRNA expressions of brain specific fatty acid protein 7 (fabp-7) and phospholipase A2 group IV (pla2g4) were significantly downregulated in AChE-deficient mice. These results suggested that AChE may play a role in neurogenesis and neurodegeneration by specifically regulating lipid metabolism in the brain.
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Arai Y, Funatsu N, Numayama-Tsuruta K, Nomura T, Nakamura S, Osumi N (2005) Role of Fabp7, a downstream gene of Pax6, in the maintenance of neuroepithelial cells during early embryonic development of the rat cortex. J Neurosci 25:9752–9761
Balsinde J, Balboa MA, Dennis EA (1997) Inflammatory activation of arachidonic acid signaling in murine P388D1 macrophages via sphingomyelin synthesis. J Biol Chem 272:20373–20377
Camp S, Zhang L, Marquez M, de la Torre B, Long JM, Bucht G, Taylor P (2005) Acetylcholinesterase (AChE) gene modification in transgenic animals: functional consequences of selected exon and regulatory region deletion. Chem Biol Interact 157–158:79–86
Capper EA, Marshall LA (2001) Mammalian phospholipases A2: mediators of inflammation, proliferation and apoptosis. Prog Lipid Res 40:167–197
Chatonnet F, Boudinot E, Chatonnet A, Taysse L, Daulon S, Champagnat J, Foutz AS (2003) Respiratory survival mechanisms in acetylcholinesterase knockout mouse. Eur J Neurosci 18:1419–1427
Chmurzynska A (2006) The multigene family of fatty acid-binding proteins (FABPs): function, structure and polymorphism. J Appl Genet 47:39–48
Dagai L, Peri-Naor R, Birk RZ (2009) Docosahexaenoic acid significantly stimulates immediate early response genes and neurite outgrowth. Neurochem Res 34:867–875
Duysen EG, Fry DL, Lockridge O (2002) Early weaning and culling eradicated Helicobacter hepaticus from an acetylcholinesterase knockout 129S6/SvEvTac mouse colony. Comp Med 52:461–466
Farooqui AA, Ong WY, Horrocks LA (2004) Biochemical aspects of neurodegeneration in human brain: involvement of neural membrane phospholipids and phospholipases A2. Neurochem Res 29:1961–1977
Fatehi M, Rowan EG, Harvey AL (2002) An electrophysiological study on the effects of Pa-1G (a phospholipase A2) from the venom of king brown snake, Pseudechis australis, on neuromuscular function. Toxicon 40:69–75
Feng L, Hatten ME, Heintz N (1994) Brain lipid-binding protein (BLBP): a novel signaling system in the developing mammalian CNS. Neuron 12:895–908
Fenton WS, Hibbeln J, Knable M (2000) Essential fatty acids, lipid membrane abnormalities, and the diagnosis and treatment of schizophrenia. Biol Psychiatry 47:8–21
Girard E, Barbier J, Chatonnet A, Krejci E, Molgo J (2005) Synaptic remodeling at the skeletal neuromuscular junction of acetylcholinesterase knockout mice and its physiological relevance. Chem Biol Interact 157–158:87–96
Haunerland NH, Spener F (2004) Fatty acid-binding proteins—insights from genetic manipulations. Prog Lipid Res 43:328–349
Kusakabe T, Maeda M, Hoshi N, Sugino T, Watanabe K, Fukuda T, Suzuki T (2000) Fatty acid synthase is expressed mainly in adult hormone-sensitive cells or cells with high lipid metabolism and in proliferating fetal cells. J Histochem Cytochem 48:613–622
Li B, Duysen EG, Volpicelli-Daley LA, Levey AI, Lockridge O (2003) Regulation of muscarinic acetylcholine receptor function in acetylcholinesterase knockout mice. Pharmacol Biochem Behav 74:977–986
Li Q, Wang M, Tan L, Wang C, Ma J, Li N, Li Y, Xu G, Li J (2005) Docosahexaenoic acid changes lipid composition and interleukin-2 receptor signaling in membrane rafts. J Lipid Res 46:1904–1913
Liu RZ, Denovan-Wright EM, Degrave A, Thisse C, Thisse B, Wright JM (2004) Differential expression of duplicated genes for brain-type fatty acid-binding proteins (fabp7a and fabp7b) during early development of the CNS in zebrafish (Danio rerio). Gene Expr Patterns 4:379–387
Meshorer E, Soreq H (2006) Virtues and woes of AChE alternative splicing in stress-related neuropathologies. Trends Neurosci 29:216–224
Minic J, Chatonnet A, Krejci E, Molgo J (2003) Butyrylcholinesterase and acetylcholinesterase activity and quantal transmitter release at normal and acetylcholinesterase knockout mouse neuromuscular junctions. Br J Pharmacol 138:177–187
Ofek K, Schoknecht K, Melamed-Book N, Heinemann U, Friedman A, Soreq H (2012) Fluoxetine induces vasodilatation of cerebral arterioles by co-modulating NO/muscarinic signalling. J Cell Mol Med 16:2736–2744
Owada Y, Abdelwahab SA, Kitanaka N, Sakagami H, Takano H, Sugitani Y, Sugawara M, Kawashima H, Kiso Y, Mobarakeh JI, Yanai K, Kaneko K, Sasaki H, Kato H, Saino-Saito S, Matsumoto N, Akaike N, Noda T, Kondo H (2006) Altered emotional behavioral responses in mice lacking brain-type fatty acid-binding protein gene. Eur J Neurosci 24:175–187
Rice SG, Nowak L, Duysen EG, Lockridge O, Lahiri DK, Reyes PF (2007) Neuropathological and immunochemical studies of brain parenchyma in acetylcholinesterase knockout mice: implications in Alzheimer’s disease. J Alzheimers Dis 11:481–489
Schmid RS, Yokota Y, Anton ES (2006) Generation and characterization of brain lipid-binding protein promoter-based transgenic mouse models for the study of radial glia. Glia 53:345–351
Shaked I, Meerson A, Wolf Y, Avni R, Greenberg D, Gilboa-Geffen A, Soreq H (2009) MicroRNA-132 potentiates cholinergic anti-inflammatory signaling by targeting acetylcholinesterase. Immunity 31:965–973
Smalheiser NR, Swanson DR (1996) Indomethacin and Alzheimer’s disease. Neurology 46:583
Smalheiser NR, Dissanayake S, Kapil A (1996) Rapid regulation of neurite outgrowth and retraction by phospholipase A2-derived arachidonic acid and its metabolites. Brain Res 721:39–48
Strokin M, Sergeeva M, Reiser G (2003) Docosahexaenoic acid and arachidonic acid release in rat brain astrocytes is mediated by two separate isoforms of phospholipase A2 and is differently regulated by cyclic AMP and Ca2+. Br J Pharmacol 139:1014–1022
Wainwright PE (2002) Dietary essential fatty acids and brain function: a developmental perspective on mechanisms. Proc Nutr Soc 61:61–69
Wang Y, Botolin D, Christian B, Busik J, Xu J, Jump DB (2005) Tissue-specific, nutritional, and developmental regulation of rat fatty acid elongases. J Lipid Res 46:706–715
Warren G, McKendrick M, Peet M (1999) The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurol Scand 99:112–116
Xie W, Wilder PJ, Stribley J, Chatonnet A, Rizzino A, Taylor P, Hinrichs SH, Lockridge O (1999) Knockout of one acetylcholinesterase allele in the mouse. Chem Biol Interact 119–120:289–299
Xie W, Stribley JA, Chatonnet A, Wilder PJ, Rizzino A, McComb RD, Taylor P, Hinrichs SH, Lockridge O (2000) Postnatal developmental delay and supersensitivity to organophosphate in gene-targeted mice lacking acetylcholinesterase. J Pharmacol Exp Ther 293:896–902
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Lin, HQ., Wang, Y., Chan, KL. et al. Differential Regulation of Lipid Metabolism Genes in the Brain of Acetylcholinesterase Knockout Mice. J Mol Neurosci 53, 397–408 (2014). https://doi.org/10.1007/s12031-014-0267-x
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DOI: https://doi.org/10.1007/s12031-014-0267-x