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Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease

  • Original Investigation
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Abstract

Rationale

Alzheimer disease (AD) is the leading cause of dementia in the elderly and has no known cure. Evidence suggests that reduced activity of specific subtypes of intracellular phospholipases A2 (cPLA2 and iPLA2) is an early event in AD and may contribute to memory impairment and neuropathology in the disease.

Objective

The objective of this study was to review the literature focusing on the therapeutic role of PLA2 stimulation by cognitive training and positive modulators, or of supplementation with arachidonic acid (PLA2 product) in facilitating memory function and synaptic transmission and plasticity in either research animals or human subjects.

Methods

MEDLINE database was searched (no date restrictions) for published articles using the keywords Alzheimer disease (mild, moderate, severe), mild cognitive impairment, healthy elderly, rats, mice, phospholipase A2, phospholipid metabolism, phosphatidylcholine, arachidonic acid, cognitive training, learning, memory, long-term potentiation, protein kinases, dietary lipid compounds, cell proliferation, neurogenesis, and neuritogenesis. Reference lists of the identified articles were checked to select additional studies of interest.

Results

Overall, the data suggest that PLA2 activation is induced in the healthy brain during learning and memory. Furthermore, learning seems to regulate endogenous neurogenesis, which has been observed in AD brains. Finally, PLA2 appears to be implicated in homeostatic processes related to neurite outgrowth and differentiation in both neurodevelopmental processes and response to neuronal injury.

Conclusion

The use of positive modulators of PLA2 (especially of cPLA2 and iPLA2) or supplementation with dietary lipid compounds (e.g., arachidonic acid) in combination with cognitive training could be a valuable therapeutic strategy for cognitive enhancement in early-stage AD.

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References

  • Abrisqueta-Gomez J, Canali F, Vieira VL, Aguiar AC, Ponce CS, Brucki SM, Bueno OF (2004) A longitudinal study of a neuropsychological rehabilitation program in Alzheimer's disease. Arq Neuropsiquiatr 62:778–783

    PubMed  Google Scholar 

  • Akiba S, Mizunaga S, Kume K, Hayama M, Sato T (1999) Involvement of group VI Ca2+-independent phospholipase A2 in protein kinase C-dependent arachidonic acid liberation in zymosan-stimulated macrophage-like P388D1 cells. J Biol Chem 274:19906–19912

    PubMed  CAS  Google Scholar 

  • Alonso M, Viola H, Izquierdo I, Medina JH (2002) Aversive experiences are associated with a rapid and transient activation of ERKs in the rat hippocampus. Neurobiol Learn Mem 77:119–124

    PubMed  Google Scholar 

  • Alonso M, Bevilaqua LR, Izquierdo I, Medina JH, Cammarota M (2003) Memory formation requires p38MAPK activity in the rat hippocampus. Neuroreport 14:1989–1992

    PubMed  CAS  Google Scholar 

  • Ambrogini P, Cuppini R, Cuppini C, Ciaroni S, Cecchini T, Ferri P, Sartini S, Del Grande P (2000) Spatial learning affects immature granule cell survival in adult rat dentate gyrus. Neurosci Lett 286:21–24

    PubMed  CAS  Google Scholar 

  • Arioka M, Cheon SH, Ikeno Y, Nakashima S, Kitamoto K (2005) A novel neurotrophic role of secretory phospholipases A2 for cerebellar granule neurons. FEBS Lett 579:2693–2701

    PubMed  CAS  Google Scholar 

  • Avila R, Bottino CM, Carvalho IA, Santos CB, Seral C, Miotto EC (2004) Neuropsychological rehabilitation of memory deficits and activities of daily living in patients with Alzheimer's disease: a pilot study. Braz J Med Biol Res 37(11):1721–1729

    PubMed  CAS  Google Scholar 

  • Barbour B, Szatkowski M, Ingledew N, Attwell D (1989) Arachidonic acid induces a prolonged inhibition of glutamate uptake into glial cells. Nature 342:918–920

    PubMed  CAS  Google Scholar 

  • Baudry M, Massicotte G, Hauge S (1991) Opposite effects of phospholipase A2 on [3H]AMPA binding in adult and neonatal membranes. Brain Res Dev Brain Res 61:265–267

    PubMed  CAS  Google Scholar 

  • Belleville S, Gilbert B, Fontaine F, Gagnon L, Ménard E, Gauthier S (2006) Improvement of episodic memory in persons with mild cognitive impairment and healthy older adults: evidence from a cognitive intervention program. Dement Geriatr Cogn Disord 22:486–499

    PubMed  Google Scholar 

  • Bengzon J, Kokaia Z, Elmér E, Nanobashvili A, Kokaia M, Lindvall O (1997) Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. Proc Natl Acad Sci U S A 94:10432–10437

    PubMed  CAS  Google Scholar 

  • Bernabeu R, Izquierdo I, Cammarota M, Jerusalinsky D, Medina JH (1995) Learning-specific, time-dependent increase in [3H]phorbol dibutyrate binding to protein kinase C in selected regions of the rat brain. Brain Res 685:163–168

    PubMed  CAS  Google Scholar 

  • Bernabeu R, Cammarota M, Izquierdo I, Medina JH (1997) Involvement of hippocampal AMPA glutamate receptor changes and the cAMP/protein kinase A/CREB-P signalling pathway in memory consolidation of an avoidance task in rats. Braz J Med Biol Res 30:961–965

    PubMed  CAS  Google Scholar 

  • Bernard J, Lahsaini A, Baudry M, Massicotte G (1993) The phospholipase A2 inhibitor bromophenacyl bromide prevents the depolarization-induced increase in [3H]AMPA binding in rat brain synaptoneurosomes. Brain Res 628:340–344

    PubMed  CAS  Google Scholar 

  • Bernard J, Lahsaini A, Massicotte G (1994) Potassium-induced long-term potentiation in area CA1 of the hippocampus involves phospholipase activation. Hippocampus 4:447–453

    PubMed  CAS  Google Scholar 

  • Bernard J, Chabot C, Gagne J, Baudry M, Massicotte G (1995) Melittin increases AMPA receptor affinity in rat brain synaptoneurosomes. Brain Res 671:195–200

    PubMed  CAS  Google Scholar 

  • Bezzi P, Carmifnoto G, Pasti L, Vesce S, Rossi D, Lodi Rizzini B, Pozzan T, Volterra A (1998) Prostaglandins stimulate calcium-dependent glutamate release in astrocytes. Nature 391:281–285

    PubMed  CAS  Google Scholar 

  • Blusztajn JK, Holbrook PG, Lakher M, Liscovitch M, Maire JC, Mauron C, Richardson UI, Tacconi M, Wurtman RJ (1986) “Autocannibalism” of membrane choline-phospholipids: physiology and pathology. Psychopharmacol Bull 22:781–786

    PubMed  CAS  Google Scholar 

  • Blusztajn JK, Liscovitch M, Mauron C, Richardson UI, Wurtman RJ (1987a) Phosphatidylcholine as a precursor of choline for acetylcholine synthesis. J Neural Transm 24:247–259

    CAS  Google Scholar 

  • Blusztajn JK, Liscovitch M, Richardson UI (1987b) Synthesis of acetylcholine from choline derived from phosphatidylcholine in a human neuronal cell line. Proc Natl Acad Sci USA 84:5474–5477

    PubMed  CAS  Google Scholar 

  • Bosetti F, Weerasinghe GR (2003) The expression of brain cyclooxygenase-2 is down-regulated in the cytosolic phospholipase A2 knockout mouse. J Neurochem 87:1471–1477

    PubMed  CAS  Google Scholar 

  • Brown GG, Levine SR, Gorell JM, Pettegrew JW, Gdowski JW, Bueri JA, Helpern JA, Welch KM (1989) In vivo 31P NMR profiles of Alzheimer's disease and multiple subcortical infarct dementia. Neurology 39:1423–1427

    PubMed  CAS  Google Scholar 

  • Cameron HA, Tanapat P, Gould E (1998) Adrenal steroids and N-methyl-D-aspartate receptor activation regulate neurogenesis in the dentate gyrus of adult rats through a common pathway. Neuroscience 82:349–354

    PubMed  CAS  Google Scholar 

  • Cammarota M, Izquierdo I, Wolfman C, Levi de Stein M, Bernabeu R, Jerusalinsky D, Medina JH (1995) Inhibitory avoidance training induces rapid and selective changes in 3[H]AMPA receptor binding in the rat hippocampal formation. Neurobiol Learn Mem 64:257–264

    PubMed  CAS  Google Scholar 

  • Cammarota M, Bernabeu R, Izquierdo I, Medina JH (1996) Reversible changes in hippocampal 3H-AMPA binding following inhibitory avoidance training in the rat. Neurobiol Learn Mem 66:85–88

    PubMed  CAS  Google Scholar 

  • Cammarota M, Paratcha G, Levi de Stein M, Bernabeu R, Izquierdo I, Medina JH (1997) B-50/GAP-43 phosphorylation and PKC activity are increased in rat hippocampal synaptosomal membranes after an inhibitory avoidance training. Neurochem Res 22:499–505

    PubMed  CAS  Google Scholar 

  • Cammarota M, Bernabeu R, Levi De Stein M, Izquierdo I, Medina JH (1998) Learning-specific, time-dependent increases in hippocampal Ca2+/calmodulin-dependent protein kinase II activity and AMPA GluR1 subunit immunoreactivity. Eur J Neurosci 10:2669–2676

    PubMed  CAS  Google Scholar 

  • Cammarota M, de Stein ML, Paratcha G, Bevilaqua LR, Izquierdo I, Medina JH (2000) Rapid and transient learning-associated increase in NMDA NR1 subunit in the rat hippocampus. Neurochem Res 25:567–572

    PubMed  CAS  Google Scholar 

  • Caporaso GL, Gandy SE, Buxbaum JD, Ramabhadran TV, Greengard P (1992) Protein phosphorylation regulates secretion of Alzheimer β/A4 amyloid precursor protein. Proc Natl Acad Sci USA 89:3055–3059

    PubMed  CAS  Google Scholar 

  • Catania MV, Hollingsworth Z, Penney JB, Young AB (1993) Phospholipase A2 modulates different subtypes of excitatory amino acid receptors: autoradiographic evidence. J Neurochem 60:236–245

    PubMed  CAS  Google Scholar 

  • Chabot C, Gagne J, Giguere C, Bernard J, Baudry M, Massicotte G (1998) Bidirectional modulation of AMPA receptor properties by exogenous phospholipase A2 in the hippocampus. Hippocampus 8:299–309

    PubMed  CAS  Google Scholar 

  • Chakraborti S (2003) Phospholipase A2 isoforms: a perspective. Cell Signal 15:637–665

    PubMed  CAS  Google Scholar 

  • Chantal S, Labelle M, Bouchard RW, Braun CM, Boulanger Y (2002) Correlation of regional proton magnetic resonance spectroscopic metabolic changes with cognitive deficits in mild Alzheimer disease. Arch Neurol 59:955–962

    PubMed  Google Scholar 

  • Chen J, Engle SJ, Seilhamer JJ, Tischfield JA (1994) Cloning and recombinant expression of a novel human low molecular weight Ca2+-dependent phospholipase A2. J Biol Chem 269:2365–2368

    PubMed  CAS  Google Scholar 

  • Chen X, Garelick MG, Wang H, Lil V, Athos J, Storm DR (2005) PI3 kinase signaling is required for retrieval and extinction of contextual memory. Nat Neurosci 8:925–931

    PubMed  CAS  Google Scholar 

  • Chen Q, Nakajima A, Choi SH, Xiong X, Sisodia SS, Tang YP (2008) Adult neurogenesis is functionally associated with AD-like neurodegeneration. Neurobiol Dis 29:316–326

    PubMed  CAS  Google Scholar 

  • Cho HW, Kim JH, Choi S, Kim HJ (2006) Phospholipase A2 is involved in muscarinic receptor-mediated sAPPα release independently of cyclooxygenase or lypoxygenase activity in SH-SY5Y cells. Neurosci Lett 397:214–218

    PubMed  CAS  Google Scholar 

  • Clare L, Wilson BA, Carter G, Roth I, Hodges JR (2002) Relearning face-name associations in early Alzheimer's disease. Neuropsychology 16:538–547

    PubMed  Google Scholar 

  • Clements MP, Rose SP (1996) Time-dependent increase in release of arachidonic acid following passive avoidance training in the day-old chick. J Neurochem 67:1317–1323

    PubMed  CAS  Google Scholar 

  • Clements MP, Bliss TV, Lynch MA (1991) Increase in arachidonic acid concentration in a postsynaptic membrane fraction following the induction of long-term potentiation in the dentate gyrus. Neuroscience 45:379–389

    PubMed  CAS  Google Scholar 

  • Colangelo V, Schurr J, Ball MJ, Pelaez RP, Bazan NG, Lukiw WJ (2002) Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down regulation and upregulation of apoptotic and pro-inflammatory signaling. J Neurosci Res 70:462–473

    PubMed  CAS  Google Scholar 

  • Conquer JA, Tierney MC, Zecevic J, Bettger WJ, Fisher RH (2000) Fatty acid analysis of blood plasma of patients with Alzheimer's disease, other types of dementia, and cognitive impairment. Lipids 35:1305–1312

    PubMed  CAS  Google Scholar 

  • Cuénod CA, Kaplan DB, Michot JL, Jehenson P, Leroy-Willig A, Forette F, Syrota A, Boller F (1995) Phospholipid abnormalities in early Alzheimer's disease. In vivo phosphorus 31 magnetic resonance spectroscopy. Arch Neurol 52:89–94

    PubMed  Google Scholar 

  • Dalla C, Bangasser DA, Edgecomb C, Shors TJ (2007) Neurogenesis and learning: acquisition and asymptotic performance predict how many new cells survive in the hippocampus. Neurobiol Learn Mem 88:143–148

    PubMed  CAS  Google Scholar 

  • Dennis EA (1994) Diversity of group types, regulation, and function of phospholipase A2. J Biol Chem 269:13057–13060

    PubMed  CAS  Google Scholar 

  • Dennis EA (1997) The growing phospholipase A2 superfamily of signal transduction enzymes. Trends Biochem Sci 22:1–2

    PubMed  CAS  Google Scholar 

  • Dupret D, Fabre A, Döbrössy MD, Panatier A, Rodríguez JJ, Lamarque S, Lemaire V, Oliet SH, Piazza PV, Abrous DN (2007) Spatial learning depends on both the addition and removal of new hippocampal neurons. PLoS Biol 5:e214

    PubMed  Google Scholar 

  • Emmerling MR, Moore CJ, Doyle PD, Carroll RT, Davis RE (1993) Phospholipase A2 activation influences the processing and secretion of the amyloid precursor protein. Biochem Biophys Res Commun 197:292–297

    PubMed  CAS  Google Scholar 

  • Emmerling MR, Dudley DT, Dyer RD, Carroll RT, Doyle PD, Davis RE (1996) The role of arachidonic acid in the secretion of the amyloid precursor protein (APP). Ann N Y Acad Sci 777:310–315

    PubMed  CAS  Google Scholar 

  • Epp JR, Spritzer MD, Galea LA (2007) Hippocampus-dependent learning promotes survival of new neurons in the dentate gyrus at a specific time during cell maturation. Neuroscience 149:273–285

    PubMed  CAS  Google Scholar 

  • Farooqui AA, Horrocks LA (2004) Brain phospholipases A2: a perspective on the history. Prostaglandins Leukot Essent Fatty Acids 71:161–169

    PubMed  CAS  Google Scholar 

  • Farooqui AA, Horrocks LA (2006) Phospholipase A2-generated lipid mediators in the brain: the good, the bad, and the ugly. Neuroscientist 12:245–260

    PubMed  CAS  Google Scholar 

  • Fluhrer R, Capell A, Westmeyer G, Willem M, Hartung B, Condron MM, Teplow DB, Haass C, Walter J (2002) A non-amyloidogenic function of BACE-2 in the secretory pathway. J Neurochem 81:1011–1020

    PubMed  CAS  Google Scholar 

  • Forlenza OV, Wacker P, Nunes PV, Yacubian J, Castro CC, Otaduy MC, Gattaz WF (2005) Reduced phospholipid breakdown in Alzheimer's brains: a 31P spectroscopy study. Psychopharmacology (Berl) 180:359–365

    CAS  Google Scholar 

  • Forlenza OV, Mendes CT, Marie SK, Gattaz WF (2007) Inhibition of phospholipase A2 reduces neurite outgrowth and neuronal viability. Prostaglandins Leukot Essent Fatty Acids 76:47–55

    PubMed  CAS  Google Scholar 

  • Fujita S, Ikegaya Y, Nishiyama N, Matsuki N (2000) Ca2+-independent phospholipase A2 inhibitor impairs spatial memory of mice. Jpn J Pharmacol 83:277–278

    PubMed  CAS  Google Scholar 

  • Fukaya T, Gondaira T, Kashiyae Y, Kotani S, Ishikura Y, Fujikawa S, Kiso Y, Sakakibara M (2007) Arachidonic acid preserves hippocampal neuron membrane fluidity in senescent rats. Neurobiol Aging 28:1179–1186

    PubMed  CAS  Google Scholar 

  • Fukushima D, Konishi M, Maruyama K, Miyamoto T, Ishiura S, Suzuki K (1993) Activation of the secretory pathway leads to a decrease in the intracellular amyloidogenic fragments generated from the amyloid protein precursor. Biochem Biophys Res Commun 194:202–207

    PubMed  CAS  Google Scholar 

  • Gan L, Qiao S, Lan X, Chi L, Luo C, Lien L, Yan Liu Q, Liu R (2008) Neurogenic responses to amyloid-β plaques in the brain of Alzheimer's disease-like transgenic (pPDGF-APPSw,Ind) mice. Neurobiol Dis 29:71–80

    PubMed  CAS  Google Scholar 

  • Gattaz WF, Maras A, Cairns NJ, Levy R, Forstl H (1995a) Decreased phospholipase A2 activity in Alzheimer brains. Biol Psychiatry 37:13–17

    PubMed  CAS  Google Scholar 

  • Gattaz WF, Steudle A, Maras A (1995b) Increased platelet phospholipase A2 in schizophrenia. Schizophr Res 16:1–6

    PubMed  CAS  Google Scholar 

  • Gattaz WF, Cairns NJ, Levy R, Forstl H, Braus DF, Maras A (1996) Decreased phospholipase A2 activity in the brain and in platelets of patients with Alzheimer's disease. Eur Arch Psychiatry Clin Neurosci 246:129–131

    PubMed  CAS  Google Scholar 

  • Gattaz WF, Forlenza OV, Talib LL, Barbosa NR, Bottino CM (2004) Platelet phospholipase A2 activity in Alzheimer’s disease and mild cognitive impairment. J Neural Transm 111:591–601

    PubMed  CAS  Google Scholar 

  • Gaudreault SB, Chabot C, Gratton JP, Poirier J (2004) The caveolin scaffolding domain modifies 2-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor binding properties by inhibiting phospholipase A2 activity. J Biol Chem 279:356–362

    PubMed  CAS  Google Scholar 

  • Gelb MH, Valentin E, Ghomashchi F, Lazdunski M, Lambeau G (2000) Cloning and recombinant expression of a structurally novel human secreted phospholipase A2. J Biol Chem 275:39823–39826

    PubMed  CAS  Google Scholar 

  • Gonzalez RG, Guimaraes AR, Moore GJ, Crawley A, Cupples LA, Growdon JH (1996) Quantitative in vivo 31P magnetic resonance spectroscopy of Alzheimer disease. Alzheimer Dis Assoc Disord 10:46–52

    PubMed  CAS  Google Scholar 

  • Gordon RD, Leighton IA, Campbell DG, Cohen P, Creaney A, Wilton DC, Masters DJ, Ritchie GA, Mott R, Taylor IW, Bundell KR, Douglas L, Morten J, Needham M (1996) Cloning and expression of cystolic phospholipase A2 (cPLA2) and a naturally occurring variant. Phosphorylation of Ser505 of recombinant cPLA2 by p42 mitogen-activated protein kinase results in an increase in specific activity. Eur J Biochem 238:690–697

    PubMed  CAS  Google Scholar 

  • Gould E, Tanapat P (1997) Lesion-induced proliferation of neuronal progenitors in the dentate gyrus of the adult rat. Neuroscience 80:427–436

    PubMed  CAS  Google Scholar 

  • Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999a) Learning enhances adult neurogenesis in the hippocampal formation. Nat Neurosci 2:260–265

    PubMed  CAS  Google Scholar 

  • Gould E, Reeves AJ, Graziano MS, Gross CG (1999b) Neurogenesis in the neocortex of adult primates. Science 286:548–552

    PubMed  CAS  Google Scholar 

  • Gould E, Tanapat P, Hastings NB, Shors TJ (1999c) Neurogenesis in adulthood: a possible role in learning. Trends Cogn Sci 3:186–192

    PubMed  Google Scholar 

  • Gray WP, Sundstrom LE (1998) Kainic acid increases the proliferation of granule cell progenitors in the dentate gyrus of the adult rat. Brain Res 790:52–59

    PubMed  CAS  Google Scholar 

  • Hölscher C (1995a) Inhibitors of cyclooxygenases produce amnesia for a passive avoidance task in the chick. Eur J Neurosci 7:1360–1365

    PubMed  Google Scholar 

  • Hölscher C (1995b) Prostaglandins play a role in memory consolidation in the chick. Eur J Pharmacol 294:253–259

    PubMed  Google Scholar 

  • Hölscher C, Rose SP (1994) Inhibitors of phospholipase A2 produce amnesia for a passive avoidance task in the chick. Behav Neural Biol 61:225–232

    PubMed  Google Scholar 

  • Hölscher C, Canevari L, Richter-Levin G (1995) Inhibitors of PLA2 and NO synthase cooperate in producing amnesia of a spatial task. Neuroreport 6:730–732

    PubMed  Google Scholar 

  • Ikeno Y, Konno N, Cheon SH, Bolchi A, Ottonello S, Kitamoto K, Arioka M (2005) Secretory phospholipases A2 induce neurite outgrowth in PC12 cells through lysophosphatidylcholine generation and activation of G2A receptor. J Biol Chem 280:28044–28052

    PubMed  CAS  Google Scholar 

  • Ikeuchi Y, Nishizaki T, Matsuoka T, Sumikawa K (1997) Long-lasting enhancement of ACh receptor currents by lysophospholipids. Molecular Brain Research 45:317–320

    PubMed  CAS  Google Scholar 

  • Jessen F, Block W, Traber F, Keller E, Flacke S, Papassotiropoulos A, Lamerichs R, Heun R, Schild HH (2000) Proton MR spectroscopy detects a relative decrease of N-acetylaspartate in the medial temporal lobe of patients with AD. Neurology 55:684–688

    PubMed  CAS  Google Scholar 

  • Jiang W, Gu W, Brännström T, Rosqvist R, Wester P (2001) Cortical neurogenesis in adult rats after transient middle cerebral artery occlusion. Stroke 32:1201–1207

    PubMed  CAS  Google Scholar 

  • Jin K, Minami M, Lan JQ, Mao XO, Batteur S, Simon RP, Greenberg DA (2001) Neurogenesis in dentate subgranular zone and rostral subventricular zone after focal cerebral ischemia in the rat. Proc Natl Acad Sci U S A 98:4710–4715

    PubMed  CAS  Google Scholar 

  • Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA (2004) Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A 101:343–347

    PubMed  CAS  Google Scholar 

  • Kadoyama K, Takahashi Y, Higashida H, Tanabe T, Yoshimoto T (2001) Cyclooxygenase-2 stimulates production of amyloid β-peptide in neuroblastoma x glioma hybrid NG108–15 cells. Biochem Biophys Res Commun 281:483–490

    PubMed  CAS  Google Scholar 

  • Kantarci K, Jack CR Jr, Xu YC, Campeau NG, O'Brien PC, Smith GE, Ivnik RJ, Boeve BF, Kokmen E, Tangalos EG, Petersen RC (2000) Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: A 1H MRS study. Neurology 55:210–217

    PubMed  CAS  Google Scholar 

  • Kantarci K, Reynolds G, Petersen RC, Boeve BF, Knopman DS, Edland SD, Smith GE, Ivnik RJ, Tangalos EG, Jack CR Jr (2003) Proton MR spectroscopy in mild cognitive impairment and Alzheimer disease: comparison of 1.5 and 3 T. AJNR Am J Neuroradiol 24:843–849

    PubMed  Google Scholar 

  • Kee NJ, Preston E, Wojtowicz JM (2001) Enhanced neurogenesis after transient global ischemia in the dentate gyrus of the rat. Exp Brain Res 136:313–320

    PubMed  CAS  Google Scholar 

  • Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal neurons in adult mice living in an enriched environment. Nature 386:493–495

    PubMed  CAS  Google Scholar 

  • Kempermann G, Brandon EP, Gage FH (1998a) Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus. Curr Biol 8:939–942

    PubMed  CAS  Google Scholar 

  • Kempermann G, Kuhn HG, Gage FH (1998b) Experience-induced neurogenesis in the senescent dentate gyrus. J Neurosci 18:3206–3212

    PubMed  CAS  Google Scholar 

  • Kishimoto K, Matsumura K, Kataoka Y, Morii H, Watanabe Y (1999) Localization of cytosolic phospholipase A2 messenger RNA mainly in neurons in the rat brain. Neuroscience 92:1061–1077

    PubMed  CAS  Google Scholar 

  • Kotani S, Nakazawa H, Tokimasa T, Akimoto K, Kawashima H, Toyoda-Ono Y, Kiso Y, Okaichi H, Sakakibara M (2003) Synaptic plasticity preserved with arachidonic acid diet in aged rats. Neurosci Res 46:453–461

    PubMed  CAS  Google Scholar 

  • Kotani S, Sakaguchi E, Warashina S, Matsukawa N, Ishikura Y, Kiso Y, Sakakibara M, Yoshimoto T, Guo J, Yamashima T (2006) Dietary supplementation of arachidonic and docosahexaenoic acids improves cognitive dysfunction. Neurosci Res 56:159–164

    PubMed  CAS  Google Scholar 

  • Kudo I, Murakami M (2002) Phospholipase A2 enzymes. Prostaglandins Other Lipid Mediat 68, 69:3–58

    Google Scholar 

  • Larsson PK, Claesson HE, Kennedy BP (1998) Multiple splice variants of the human calcium-independent phospholipase A2 and their effect on enzyme activity. J Biol Chem 273:207–214

    PubMed  CAS  Google Scholar 

  • Larsson Forsell PK, Kennedy BP, Claesson HE (1999) The human calcium-independent phospholipase A2 gene multiple enzymes with distinct properties from a single gene. Eur J Biochem 262:575–585

    PubMed  CAS  Google Scholar 

  • Lautens LL, Chiou XG, Sharp JD, Young WS 3rd, Sprague DL, Ross LS, Felder CC (1998) Cytosolic phospholipase A2 (cPLA2) distribution in murine brain and functional studies indicate that cPLA2 does not participate in muscarinic receptor-mediated signaling in neurons. Brain Res 809:18–30

    PubMed  CAS  Google Scholar 

  • Lazarewicz JW, Salinska E, Wroblewski JT (1992) NMDA receptor-mediated arachidonic acid release in neurons: role in signal transduction and pathological aspects. Adv Exp Med Biol 318:73–89

    PubMed  CAS  Google Scholar 

  • Lim SY, Suzuki H (2000a) Effect of dietary docosahexaenoic acid and phosphatidylcholine on maze behavior and fatty acid composition of plasma and brain lipids in mice. Int J Vitam Nutr Res 70:251–259

    PubMed  CAS  Google Scholar 

  • Lim SY, Suzuki H (2000b) Intakes of dietary docosahexaenoic acid ethyl ester and egg phosphatidylcholine improve maze-learning ability in young and old mice. J Nutr 130:1629–1632

    PubMed  CAS  Google Scholar 

  • Lim SY, Suzuki H (2002) Dose-response effect of egg-phosphatidylcholine on maze-learning ability and fatty acid composition of plasma and brain in aged mice fed an n-3 fatty acid-deficient diet. Ann Nutr Metab 46:215–221

    PubMed  CAS  Google Scholar 

  • Lin LL, Wartmann M, Lin AY, Knopf JL, Seth A, Davis RJ (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72:269–278

    PubMed  CAS  Google Scholar 

  • López-Toledano MA, Shelanski ML (2007) Increased neurogenesis in young transgenic mice overexpressing human APP(Sw, Ind). J Alzheimers Dis 12:229–240

    PubMed  Google Scholar 

  • Maire JC, Wurtman RJ (1985) Effects of electrical stimulation and choline availability on the release and contents of acetylcholine and choline in superfused slices from rat striatum. J Physiol (Paris) 80:189–195

    CAS  Google Scholar 

  • Mancuso DJ, Jenkins CM, Gross RW (2000) The genomic organization, complete mRNA sequence, cloning, and expression of a novel human intracellular membrane-associated calcium-independent phospholipase A2. J Biol Chem 275:9937–9945

    PubMed  CAS  Google Scholar 

  • Martel MA, Patenaude C, Menard C, Alaux S, Cummings BS, Massicotte G (2006) A novel role for calcium-independent phospholipase A in α-amino-3-hydroxy-5-methylisoxazole-propionate receptor regulation during long-term potentiation. Eur J Neurosci 23:505–513

    PubMed  Google Scholar 

  • Massicotte G, Baudry M (1990) Modulation of DL-α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA)/quisqualate receptors by phospholipase A2 treatment. Neurosci Lett 118:245–248

    PubMed  CAS  Google Scholar 

  • Massicotte G, Vanderklish P, Lynch G, Baudry M (1991) Modulation of DL-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/quisqualate receptors by phospholipase A2: a necessary step in long-term potentiation? Proc Natl Acad Sci U S A 88:1893–1897

    PubMed  CAS  Google Scholar 

  • Masuda S, Murakami M, Takanezawa Y, Aoki J, Arai H, Ishikawa Y, Ishii T, Arioka M, Kudo I (2005) Neuronal expression and neuritogenic action of group X secreted phospholipase A2. J Biol Chem 280:23203–23214

    PubMed  CAS  Google Scholar 

  • Masuda S, Yamamoto K, Hirabayashi T, Ishikawa Y, Ishii T, Kudo I, Murakami M (2008) Human group III secreted phospholipase A2 promotes neuronal outgrowth and survival. Biochem J 409:429–438

    PubMed  CAS  Google Scholar 

  • Miatto O, Gonzalez RG, Buonanno F, Growdon JH (1986) In vitro 31P NMR spectroscopy detects altered phospholipid metabolism in Alzheimer's disease. Can J Neurol Sci 13:535–539

    PubMed  CAS  Google Scholar 

  • Miller BL, Chang L, Booth R, Ernst T, Cornford M, Nikas D, McBride D, Jenden DJ (1996) In vivo 1H MRS choline: correlation with in vitro chemistry/histology. Life Sci 58:1929–1935

    PubMed  CAS  Google Scholar 

  • Molloy GY, Rattray M, Williams RJ (1998) Genes encoding multiple forms of phospholipase A2 are expressed in rat brain. Neurosci Lett 258:139–142

    PubMed  CAS  Google Scholar 

  • Moses GS, Jensen MD, Lue LF, Walker DG, Sun AY, Simonyi A, Sun GY (2006) Secretory PLA2-IIA: a new inflammatory factor for Alzheimer's disease. J Neuroinflammation 3:28

    PubMed  Google Scholar 

  • Mulder M, Ravid R, Swaab DF, de Kloet ER, Haasdijk ED, Julk J, van der Boom JJ, Havekes LM (1998) Reduced levels of cholesterol, phospholipids, and fatty acids in cerebrospinal fluid of Alzheimer disease patients are not related to apolipoprotein E4. Alzheimer Dis Assoc Disord 12:198–203

    PubMed  CAS  Google Scholar 

  • Muthalif MM, Hefner Y, Canaan S, Harper J, Zhou H, Parmentier JH, Aebersold R, Gelb MH, Malik KU (2001) Functional interaction of calcium-/calmodulin-dependent protein kinase II and cytosolic phospholipase A(2). J Biol Chem 276:39653–39660

    PubMed  CAS  Google Scholar 

  • Nagy Z, Esiri MM, Smith AD (1997) Expression of cell division markers in the hippocampus in Alzheimer's disease and other neurodegenerative conditions. Acta Neuropathol 93:294–300

    PubMed  CAS  Google Scholar 

  • Nalefski EA, Falke JJ (1996) The C2 domain calcium-binding motif: structural and functional diversity. Protein Sci 5:2375–2390

    Article  PubMed  CAS  Google Scholar 

  • Nalefski EA, McDonagh T, Somers W, Seehra J, Falke JJ, Clark JD (1998) Independent folding and ligand specificity of the C2 calcium-dependent lipid binding domain of cytosolic phospholipase A2. J Biol Chem 273:1365–1372

    PubMed  CAS  Google Scholar 

  • Nemenoff RA, Winitz S, Qian NX, Van Putten V, Johnson GL, Heasley LE (1993) Phosphorylation and activation of a high molecular weight form of phospholipase A2 by p42 microtubule-associated protein 2 kinase and protein kinase C. J Biol Chem 268:1960–1964

    PubMed  CAS  Google Scholar 

  • Nilsson M, Perfilieva E, Johansson U, Orwar O, Eriksson OS (1999) Enriched environment increases neurogenesis in the adult rat dentate gyrus and improves spatial memory. J Neurobiol 39:569–578

    PubMed  CAS  Google Scholar 

  • Nitsch RM, Deng A, Wurtman RJ, Growdon JH (1997) Metabotropic glutamate receptor subtype mGluR1α stimulates the secretion of the amyloid β-protein precursor ectodomain. J Neurochem 69:704–712

    PubMed  CAS  Google Scholar 

  • Ohto T, Uozumi N, Hirabayashi T, Shimizu T (2005) Identification of novel cytosolic phospholipase A2s, murine cPLA2{δ}, {ɛ}, and {ζ}, which form a gene cluster with cPLA2{β}. J Biol Chem 280:24576–24583

    PubMed  CAS  Google Scholar 

  • Okaichi Y, Ishikura Y, Akimoto K, Kawashima H, Toyoda-Ono Y, Kiso Y, Okaichi H (2005) Arachidonic acid improves aged rats’ spatial cognition. Physiol Behav 84:617–623

    PubMed  CAS  Google Scholar 

  • Owada Y, Tominaga T, Yoshimoto T, Kondo H (1994) Molecular cloning of rat cDNA for cytosolic phospholipase A2 and the increased gene expression in the dentate gyrus following transient forebrain ischemia. Brain Res Mol Brain Res 25:364–368

    PubMed  CAS  Google Scholar 

  • Paratcha G, Furman M, Bevilaqua L, Cammarota M, Vianna M, de Stein ML, Izquierdo I, Medina JH (2000) Involvement of hippocampal PKCβI isoform in the early phase of memory formation of an inhibitory avoidance learning. Brain Res 855:199–205

    PubMed  CAS  Google Scholar 

  • Pellerin L, Wolfe LS (1991) Release of arachidonic acid by NMDA-receptor activation in the rat hippocampus. Neurochem Res 16:983–989

    PubMed  CAS  Google Scholar 

  • Petersen RC, Doody R, Kurz A, Mohs RC, Morris JC, Rabins PV, Ritchie K, Rossor M, Thal L, Winblad B (2001a) Current concepts in mild cognitive impairment. Arch Neurol 58:1985–1992

    PubMed  CAS  Google Scholar 

  • Petersen RC, Stevens JC, Ganguli M, Tangalos EG, Cummings JL, DeKosky ST (2001b) Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 56:1133–1142

    PubMed  CAS  Google Scholar 

  • Pettegrew JW, Kopp SJ, Minshew NJ, Glonek T, Feliksik JM, Tow JP, Cohen MM (1987) 31P nuclear magnetic resonance studies of phosphoglyceride metabolism in developing and degenerating brain: preliminary observations. J Neuropathol Exp Neurol 46:419–430

    PubMed  CAS  Google Scholar 

  • Pettegrew JW, Moossy J, Withers G, McKeag D, Panchalingam K (1988) 31P nuclear magnetic resonance study of the brain in Alzheimer's disease. J Neuropathol Exp Neurol 47:235–248

    PubMed  CAS  Google Scholar 

  • Pettegrew JW, Panchalingam K, Klunk WE, McClure RJ, Muenz LR (1994) Alterations of cerebral metabolism in probable Alzheimer's disease: a preliminary study. Neurobiol Aging 15:117–132

    PubMed  CAS  Google Scholar 

  • Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ (1995) Clinical and neurochemical effects of acetyl-L-carnitine in Alzheimer's disease. Neurobiol Aging 16:1–4

    PubMed  CAS  Google Scholar 

  • Pickard RT, Strifler BA, Kramer RM, Sharp JD (1999) Molecular cloning of two new human paralogs of 85-kDa cytosolic phospholipase A2. J Biol Chem 274:8823–8831

    PubMed  CAS  Google Scholar 

  • Prokazova NV, Zvezdina ND, Korotaeva AA (1998) Effect of lysophosphatidylcholine on transmembrane signal transduction. Biochemistry (Mosc) 63:31–37

    CAS  Google Scholar 

  • Rall JM, Mach SA, Dash PK (2003) Intrahippocampal infusion of a cyclooxygenase-2 inhibitor attenuates memory acquisition in rats. Brain Res 968:273–276

    PubMed  CAS  Google Scholar 

  • Rapp S, Brenes G, Marsh AP (2002) Memory enhancement training for older adults with mild cognitive impairment: a preliminary study. Aging Ment Health 6:5–11

    PubMed  CAS  Google Scholar 

  • Ross BM, Moszczynska A, Erlich J, Kish SJ (1998) Phospholipid-metabolizing enzymes in Alzheimer's disease: increased lysophospholipid acyltransferase activity and decreased phospholipase A2 activity. J Neurochem 70:786–793

    PubMed  CAS  Google Scholar 

  • Rozzini L, Costardi D, Chilovi BV, Franzoni S, Trabucchi M, Padovani A (2007) Efficacy of cognitive rehabilitation in patients with mild cognitive impairment treated with cholinesterase inhibitors. Int J Geriatr Psychiatry 22:356–360

    PubMed  Google Scholar 

  • Sanfeliu C, Hunt A, Patel AJ (1990) Exposure to N-methyl-D-aspartate increases release of arachidonic acid in primary cultures of rat hippocampal neurons and not in astrocytes. Brain Res 526:241–248

    PubMed  CAS  Google Scholar 

  • Sato T, Ishida T, Irifune M, Tanaka K, Hirate K, Nakamura N, Nishikawa T (2007) Effect of NC-1900, an active fragment analog of arginine vasopressin, and inhibitors of arachidonic acid metabolism on performance of a passive avoidance task in mice. Eur J Pharmacol 560:36–41

    PubMed  CAS  Google Scholar 

  • Schaeffer EL, Gattaz WF (2005) Inhibition of calcium-independent phospholipase A2 activity in rat hippocampus impairs acquisition of short- and long-term memory. Psychopharmacology (Berl) 181:392–400

    CAS  Google Scholar 

  • Schaeffer EL, Gattaz WF (2007) Requirement of hippocampal phospholipase A2 activity for long-term memory retrieval in rats. J Neural Transm 114:379–385

    PubMed  CAS  Google Scholar 

  • Schaeffer EL, Gattaz WF (2008) Cholinergic and glutamatergic alterations beginning at the early stages of Alzheimer disease: participation of the phospholipase A(2) enzyme. Psychopharmacology (Berl) 198:1–27

    CAS  Google Scholar 

  • Sharifzadeh M, Naghdi N, Khosrovani S, Ostad SN, Sharifzadeh K, Roghani A (2005) Post-training intrahippocampal infusion of the COX-2 inhibitor celecoxib impaired spatial memory retention in rats. Eur J Pharmacol 511:159–166

    PubMed  CAS  Google Scholar 

  • Sharp JD, White DL (1993) Cytosolic PLA2: mRNA levels and potential for transcriptional regulation. J Lipid Mediat 8:183–189

    PubMed  CAS  Google Scholar 

  • Shinzawa K, Sumi H, Ikawa M, Matsuoka Y, Okabe M, Sakoda S, Tsujimoto Y (2008) Neuroaxonal dystrophy caused by group VIA phospholipase A2 deficiency in mice: a model of human neurodegenerative disease. J Neurosci 28:2212–2220

    PubMed  CAS  Google Scholar 

  • Six DA, Dennis EA (2000) The expanding superfamily of phospholipase A2 enzymes: classification and characterization. Biochim Biophys Acta 1488:1–19

    PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Smith CD, Gallenstein LG, Layton WJ, Kryscio RJ, Markesbery WR (1993) 31P magnetic resonance spectroscopy in Alzheimer's and Pick's disease. Neurobiol Aging 14:85–92

    PubMed  CAS  Google Scholar 

  • Song C, Chang XJ, Bean KM, Proia MS, Knopf JL, Kriz RW (1999) Molecular characterization of cytosolic phospholipase A2-β. J Biol Chem 274:17063–17067

    PubMed  CAS  Google Scholar 

  • Stella N, Pellerin L, Magistretti PJ (1995) Modulation of the glutamate-evoked release of arachidonic acid from mouse cortical neurons: involvement of a pH-sensitive membrane phospholipase A2. J Neurosci 15:3307–3317

    PubMed  CAS  Google Scholar 

  • Stephenson DT, Lemere CA, Selkoe DJ, Clemens JA (1996) Cytosolic phospholipase A2 (cPLA2) immunoreactivity is elevated in Alzheimer's disease brain. Neurobiol Dis 3:51–63

    PubMed  CAS  Google Scholar 

  • Stephenson D, Rash K, Smalstig B, Roberts E, Johnstone E, Sharp J, Panetta J, Little S, Kramer R, Clemens J (1999) Cytosolic phospholipase A2 is induced in reactive glia following different forms of neurodegeneration. Glia 27:110–128

    PubMed  CAS  Google Scholar 

  • Stewart MG, Bourne RC, Steele RJ (1992) Quantitative Autoradiographic Demonstration of Changes in Binding to NMDA-sensitive [3H]Glutamate and [3H]MK801, but not [3H]AMPA Receptors in Chick Forebrain 30 min After Passive Avoidance Training. Eur J Neurosci 4:936–943

    PubMed  Google Scholar 

  • Suzuki N, Ishizaki J, Yokota Y, Higashino K, Ono T, Ikeda M, Fujii N, Kawamoto K, Hanasaki K (2000) Structures, enzymatic properties, and expression of novel human and mouse secretory phospholipase A2s. J Biol Chem 275:5785–5793

    PubMed  CAS  Google Scholar 

  • Talbot K, Young RA, Jolly-Tornetta C, Lee VM, Trojanowski JQ, Wolf BA (2000) A frontal variant of Alzheimer's disease exhibits decreased calcium-independent phospholipase A2 activity in the prefrontal cortex. Neurochem Int 37:17–31

    PubMed  CAS  Google Scholar 

  • Talib LL, Yassuda MS, Diniz BSO, Forlenza OV, Gattaz WF (2008) Cognitive training increases platelet PLA2 activity in healthy elderly subjects. Prostaglandins Leukotrienes and Essential Fatty Acids 78:265–269

    CAS  Google Scholar 

  • Tanaka H, Takeya R, Sumimoto H (2000) A novel intracellular membrane-bound calcium-independent phospholipase A2. Biochem Biophys Res Commun 272:320–326

    PubMed  CAS  Google Scholar 

  • Teather LA, Packard MG, Bazan NG (2002) Post-training cyclooxygenase-2 (COX-2) inhibition impairs memory consolidation. Learn Mem 9:41–47

    PubMed  Google Scholar 

  • Tocco G, Massicotte G, Standley S, Thompson RF, Baudry M (1992) Phospholipase A2-induced changes in AMPA receptor: an autoradiographic study. Neuroreport 3:515–518

    PubMed  CAS  Google Scholar 

  • Underwood KW, Song C, Kriz RW, Chang XJ, Knopf JL, Lin LL (1998) A novel calcium-independent phospholipase A2, cPLA2-γ, that is prenylated and contains homology to cPLA2. J Biol Chem 273:21926–21932

    PubMed  CAS  Google Scholar 

  • Valenzuela MJ, Jones M, Wen W, Rae C, Graham S, Schnier R, Sachdev P (2003) Memory training alters hippocampal neurochemistry in healthy elderly. Neuroreport 14:1333–1337

    PubMed  Google Scholar 

  • Vázquez A, Peña de Ortiz S (2004) Lead (Pb(+)) impairs long-term memory and blocks learning-induced increases in hippocampal protein kinase C activity. Toxicol Appl Pharmacol 200:27–39

    PubMed  Google Scholar 

  • Volterra A, Trotti D, Cassutti P, Tromba C, Salvaggio A, Melcangi RC, Racagni G (1992) High sensitivity of glutamate uptake to extracellular free arachidonic acid levels in rat cortical synaptosomes and astrocytes. J Neurochem 59:600–606

    PubMed  CAS  Google Scholar 

  • Wenisch E, Cantegreil-Kallen I, De Rotrou J, Garrigue P, Moulin F, Batouche F, Richard A, De Sant'Anna M, Rigaud AS (2007) Cognitive stimulation intervention for elders with mild cognitive impairment compared with normal aged subjects: preliminary results. Aging Clin Exp Res 19:316–322

    PubMed  Google Scholar 

  • Wharton SB, Williams GH, Stoeber K, Gelsthorpe CH, Baxter L, Johnson AL, Ince PG; MRC-CFAS (2005) Expression of Ki67, PCNA and the chromosome replication licensing protein Mcm2 in glial cells of the ageing human hippocampus increases with the burden of Alzheimer-type pathology. Neurosci Lett 383:33–38

    PubMed  CAS  Google Scholar 

  • Wijkander J, Sundler R (1991) An 100-kDa arachidonate-mobilizing phospholipase A2 in mouse spleen and the macrophage cell line J774. Purification, substrate interaction and phosphorylation by protein kinase C. Eur J Biochem 202:873–880

    PubMed  CAS  Google Scholar 

  • Williams EJ, Furness J, Walsh FS, Doherty P (1994a) Characterisation of the second messenger pathway underlying neurite outgrowth stimulated by FGF. Development 120:1685–1693

    PubMed  CAS  Google Scholar 

  • Williams EJ, Walsh FS, Doherty P (1994b) The production of arachidonic acid can account for calcium channel activation in the second messenger pathway underlying neurite outgrowth stimulated by NCAM, N-cadherin, and L1. J Neurochem 62:1231–1234

    Article  PubMed  CAS  Google Scholar 

  • Winstead MV, Balsinde J, Dennis EA (2000) Calcium-independent phospholipase A2: structure and function. Biochim Biophys Acta 1488:28–39

    PubMed  CAS  Google Scholar 

  • Yamashima T, Tonchev AB, Yukie M (2007) Adult hippocampal neurogenesis in rodents and primates: endogenous, enhanced, and engrafted. Rev Neurosci 18:67–82

    PubMed  CAS  Google Scholar 

  • Yang HC, Mosior M, Ni B, Dennis EA (1999) Regional distribution, ontogeny, purification, and characterization of the Ca2+ -independent phospholipase A2 from rat brain. J Neurochem 73:1278–1287

    PubMed  CAS  Google Scholar 

  • Young E, Cesena T, Meiri KF, Perrone-Bizzozero NI (2002) Changes in protein kinase C (PKC) activity, isozyme translocation, and GAP-43 phosphorylation in the rat hippocampal formation after a single-trial contextual fear conditioning paradigm. Hippocampus 12:457–464

    PubMed  CAS  Google Scholar 

  • Yu AC, Chan PH, Fishman RA (1986) Effects of arachidonic acid on glutamate and γ-aminobutyric acid uptake in primary cultures of rat cerebral cortical astrocytes and neurons. J Neurochem 47:1181–1189

    PubMed  CAS  Google Scholar 

  • Yu AC, Chan PH, Fishman RA (1987) Arachidonic acid inhibits uptake of glutamate and glutamine but not of GABA in cultured cerebellar granule cells. J Neurosci Res 17:424–427

    PubMed  CAS  Google Scholar 

  • Zhang RL, Zhang ZG, Zhang L, Chopp M (2001) Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia. Neuroscience 105:33–41

    PubMed  CAS  Google Scholar 

  • Zhou H, Das S, Murthy KS (2003) Erk1/2- and p38 MAP kinase-dependent phosphorylation and activation of cPLA2 by m3 and m2 receptors. Am J Physiol Gastrointest Liver Physiol 284:G472–G480

    PubMed  CAS  Google Scholar 

  • Zubenko GS, Winwood E, Jacobs B, Teply I, Stiffler JS, Hughes HB 3rd, Huff FJ, Sunderland T, Martinez AJ (1999) Prospective study of risk factors for Alzheimer’s disease: results at 7.5 years. Am J Psychiatry 156:50–57

    PubMed  CAS  Google Scholar 

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Schaeffer, E.L., Forlenza, O.V. & Gattaz, W.F. Phospholipase A2 activation as a therapeutic approach for cognitive enhancement in early-stage Alzheimer disease. Psychopharmacology 202, 37–51 (2009). https://doi.org/10.1007/s00213-008-1351-0

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