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Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease

Abstract

Neuronal expression of familial Alzheimer's disease–mutant human amyloid precursor protein (hAPP) and hAPP-derived amyloid-β (Aβ) peptides causes synaptic dysfunction, inflammation and abnormal cerebrovascular tone in transgenic mice. Fatty acids may be involved in these processes, but their contribution to Alzheimer's disease pathogenesis is uncertain. We used a lipidomics approach to generate a broad profile of fatty acids in brain tissues of hAPP-expressing mice and found an increase in arachidonic acid and its metabolites, suggesting increased activity of the group IV isoform of phospholipase A2 (GIVA-PLA2). The levels of activated GIVA-PLA2 in the hippocampus were increased in individuals with Alzheimer's disease and in hAPP mice. Aβ caused a dose-dependent increase in GIVA-PLA2 phosphorylation in neuronal cultures. Inhibition of GIVA-PLA2 diminished Aβ-induced neurotoxicity. Genetic ablation or reduction of GIVA-PLA2 protected hAPP mice against Aβ-dependent deficits in learning and memory, behavioral alterations and premature mortality. Inhibition of GIVA-PLA2 may be beneficial in the treatment and prevention of Alzheimer's disease.

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Figure 1: Increased PLA2-dependent fatty acid levels in brain tissues of hAPP mice.
Figure 2: GIVA-PLA2 levels in hAPP mice and humans with Alzheimer's disease.
Figure 3: Inhibition of GIVA-PLA2 prevents Aβ1–42 toxicity in primary neuronal cultures.
Figure 4: GIVA-PLA2 reduction improves learning and memory in hAPP mice.
Figure 5: Pla2g4a reduction prevents hyperactivity, abnormal anxiety/exploration-related behavior and premature mortality in hAPP mice.
Figure 6: Reduction or removal of GIVA-PLA2 did not affect hAPP or Aβ levels in hAPP mice.

References

  1. 1

    Roberson, E.D. & Mucke, L. 100 years and counting: prospects for defeating Alzheimer's disease. Science 314, 781–784 (2006).

    Article  Google Scholar 

  2. 2

    Palop, J.J. et al. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease–related cognitive deficits. Proc. Natl. Acad. Sci. USA 100, 9572–9577 (2003).

    CAS  Article  Google Scholar 

  3. 3

    Palop, J.J., Chin, J. & Mucke, L. A network dysfunction perspective on neurodegenerative diseases. Nature 443, 768–773 (2006).

    CAS  Article  Google Scholar 

  4. 4

    Menard, C., Patenaude, C. & Massicotte, G. Phosphorylation of AMPA receptor subunits is differentially regulated by phospholipase A2 inhibitors. Neurosci. Lett. 389, 51–56 (2005).

    CAS  Article  Google Scholar 

  5. 5

    Phillis, J.W., Horrocks, L.A. & Farooqui, A.A. Cyclooxygenases, lipoxygenases and epoxygenases in CNS: their role and involvement in neurological disorders. Brain Res. Rev. 52, 201–243 (2006).

    CAS  Article  Google Scholar 

  6. 6

    Spector, A.A. & Norris, A.W. Action of epoxyeicosatrienoic acids on cellular function. Am. J. Physiol. Cell Physiol. 292, C996–C1012 (2007).

    CAS  Article  Google Scholar 

  7. 7

    Praticò, D., Uryu, K., Leight, S., Trojanowswki, J.Q. & Lee, V.M.Y. Increased lipid peroxidation precedes amyloid plaque formation in an animal model of Alzheimer amyloidosis. J. Neurosci. 21, 4183–4187 (2001).

    Article  Google Scholar 

  8. 8

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

    Article  Google Scholar 

  9. 9

    Lim, G.P. et al. A diet enriched with the omega-3 fatty acid docosahexaenoic acid reduces amyloid burden in an aged Alzheimer mouse model. J. Neurosci. 25, 3032–3040 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Freund-Levi, Y. et al. ω-3 Fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: OmegAD study: a randomized double-blind trial. Arch. Neurol. 63, 1402–1408 (2006).

    Article  Google Scholar 

  11. 11

    Yoshikawa, K., Kita, Y., Kishimoto, K. & Shimizu, T. Profiling of eicosanoid production in the rat hippocampus during kainic acid-induced seizure: dual-phase regulation and differential involvement of COX-1 and COX-2. J. Biol. Chem. 281, 14663–14669 (2006).

    CAS  Article  Google Scholar 

  12. 12

    Roberson, E.D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model. Science 316, 750–754 (2007).

    CAS  Article  Google Scholar 

  13. 13

    Palop, J.J. et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 55, 697–711 (2007).

    CAS  Article  Google Scholar 

  14. 14

    Meilandt, W.J. et al. Enkephalin elevations contribute to neuronal and behavioral impairments in a transgenic mouse model of Alzheimer's disease. J. Neurosci. 28, 5007–5017 (2008).

    CAS  Article  Google Scholar 

  15. 15

    Cheng, I.H. et al. Accelerating amyloid-β fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J. Biol. Chem. 282, 23818–23828 (2007).

    CAS  Article  Google Scholar 

  16. 16

    Hwang, D.Y. et al. Alterations in behavior, amyloid β-42, caspase-3 and COX-2 in mutant PS2 transgenic mouse model of Alzheimer's disease. FASEB J. 16, 805–813 (2002).

    CAS  Article  Google Scholar 

  17. 17

    Williams, J.H., Errington, M.L., Lynch, M.A. & Bliss, T.V.P. Arachidonic acid induces a long-term activity–dependent enhancement of synaptic transmission in the hippocampus. Nature 341, 739–742 (1989).

    CAS  Article  Google Scholar 

  18. 18

    Funk, C.D. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294, 1871–1875 (2001).

    CAS  Article  Google Scholar 

  19. 19

    Iadecola, C. Neurovascular regulation in the normal brain and in Alzheimer's disease. Nat. Rev. Neurosci. 5, 347–360 (2004).

    CAS  Article  Google Scholar 

  20. 20

    Zlokovic, B.V. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 28, 202–208 (2005).

    CAS  Article  Google Scholar 

  21. 21

    Bonventre, J.V. et al. Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2 . Nature 390, 622–625 (1997).

    CAS  Article  Google Scholar 

  22. 22

    Stephenson, D. et al. Cytosolic phospholipase A2 is induced in reactive glia following different forms of neurodegeneration. Glia 27, 110–128 (1999).

    CAS  Article  Google Scholar 

  23. 23

    Colangelo, V. et al. Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: transcription and neurotrophic factor down-regulation and up-regulation of apoptotic and pro-inflammatory signaling. J. Neurosci. Res. 70, 462–473 (2002).

    CAS  Article  Google Scholar 

  24. 24

    Gattaz, W.F. et al. Decreased phospholipase A2 activity in Alzheimer brains. Eur. Arch. Psychiatry Clin. Neurosci. 246, 129–131 (1995).

    Article  Google Scholar 

  25. 25

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

    CAS  Article  Google Scholar 

  26. 26

    Sandhya, T.L., Ong, W.Y., Horrocks, L.A. & Farooqui, A.A. A light and electron microscopic study of cytoplasmic phospholipase A2 and cyclooxygenase-2 in the hippocampus after kainate lesions. Brain Res. 788, 223–231 (1998).

    CAS  Article  Google Scholar 

  27. 27

    Malaplate-Armand, C. et al. Soluble oligomers of amyloid-β peptide induce neuronal apoptosis by activating a cPLA2-dependent sphingomyelinase-ceramide pathway. Neurobiol. Dis. 23, 178–189 (2006).

    CAS  Article  Google Scholar 

  28. 28

    Kriem, B. et al. Cytosolic phospholipase A2 mediates neuronal apoptosis induced by soluble oligomers of the amyloid-β peptide. FASEB J. 19, 85–87 (2004).

    Article  Google Scholar 

  29. 29

    Bezprozvanny, I. & Mattson, M.P. Neuronal calcium mishandling and the pathogenesis of Alzheimer's disease. Trends Neurosci. 31, 454–463 (2008).

    CAS  Article  Google Scholar 

  30. 30

    Snyder, E.M. et al. Regulation of NMDA receptor trafficking by amyloid-β. Nat. Neurosci. 8, 1051–1058 (2005).

    CAS  Article  Google Scholar 

  31. 31

    Brorson, J.R. et al. The Ca2+ influx induced by β-amyloid peptide 25–35 in cultured hippocampal neurons results from network excitation. J. Neurobiol. 26, 325–338 (1995).

    CAS  Article  Google Scholar 

  32. 32

    Hsieh, H. et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006).

    CAS  Article  Google Scholar 

  33. 33

    Blanchard, B.J., Thomas, V.L. & Ingram, V.M. Mechanism of membrane depolarization caused by the Alzheimer Aβ1–42 peptide. Biochem. Biophys. Res. Commun. 293, 1197–1203 (2002).

    CAS  Article  Google Scholar 

  34. 34

    Malenka, R.C. & Bear, M.F. LTP and LTD: an embarrassment of riches. Neuron 44, 5–21 (2004).

    CAS  Article  Google Scholar 

  35. 35

    Miller, B., Sarantis, M., Traynelis, S.F. & Attwell, D. Potentiation of NMDA receptor currents by arachidonic acid. Nature 355, 722–725 (1992).

    CAS  Article  Google Scholar 

  36. 36

    Gaudreault, S.B., Chabot, C., Gratton, J.P. & Poirier, J. 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 (2004).

    CAS  Article  Google Scholar 

  37. 37

    Carter, T.L. et al. Differential preservation of AMPA receptor subunits in the hippocampi of Alzheimer's disease patients according to Braak stage. Exp. Neurol. 187, 299–309 (2004).

    CAS  Article  Google Scholar 

  38. 38

    Ting, J.T., Kelley, B.G., Lambert, T.J., Cook, D.G. & Sullivan, J.M. Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms. Proc. Natl. Acad. Sci. USA 104, 353–358 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Kamenetz, F. et al. APP processing and synaptic function. Neuron 37, 925–937 (2003).

    CAS  Article  Google Scholar 

  40. 40

    Prasad, M.R., Mark, A.L., Mustafa, Y., Harbhajan, D. & William, R.M. Regional membrane phospholipid alterations in Alzheimer's disease. Neurochem. Res. 23, 81–88 (1998).

    CAS  Article  Google Scholar 

  41. 41

    Cutler, R.G. et al. Involvement of oxidative stress–induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc. Natl. Acad. Sci. USA 101, 2070–2075 (2004).

    CAS  Article  Google Scholar 

  42. 42

    Mark, R.J., Pang, Z., Geddes, J.W., Uchida, K. & Mattson, M.P. Amyloid β-peptide impairs glucose transport in hippocampal and cortical neurons: involvement of membrane lipid peroxidation. J. Neurosci. 17, 1046–1054 (1997).

    CAS  Article  Google Scholar 

  43. 43

    Shankar, G.M. et al. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor–dependent signaling pathway. J. Neurosci. 27, 2866–2875 (2007).

    CAS  Article  Google Scholar 

  44. 44

    Bredt, D.S. & Nicoll, R.A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).

    CAS  Article  Google Scholar 

  45. 45

    Hsia, A.Y. et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl. Acad. Sci. USA 96, 3228–3233 (1999).

    CAS  Article  Google Scholar 

  46. 46

    Shepherd, J.D. & Huganir, R.L. The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu. Rev. Cell Dev. Biol. 23, 613–643 (2007).

    CAS  Article  Google Scholar 

  47. 47

    Brady, K.M., Texel, S.J., Kishimoto, K., Koehler, R.C. & Sapirstein, A. Cytosolic phospholipase A2 α modulates NMDA neurotoxicity in mouse hippocampal cultures. Eur. J. Neurosci. 24, 3381–3386 (2006).

    Article  Google Scholar 

  48. 48

    Luria, A. et al. Compensatory mechanism for homeostatic blood pressure regulation in Ephx2 gene–disrupted mice. J. Biol. Chem. 282, 2891–2898 (2007).

    CAS  Article  Google Scholar 

  49. 49

    Rui, Y., Tiwari, P., Xie, Z. & Zheng, J.Q. Acute impairment of mitochondrial trafficking by β-amyloid peptides in hippocampal neurons. J. Neurosci. 26, 10480–10487 (2006).

    CAS  Article  Google Scholar 

  50. 50

    Lin, J.W. et al. Distinct molecular mechanisms and divergent endocytotic pathways of AMPA receptor internalization. Nat. Neurosci. 3, 1282–1290 (2000).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank the Alzheimer's Disease Research Center at University of California San Francisco for postmortem brain tissues; T. Wu, A. Thwin and H. Solanoy for technical support; C. McCulloch for help with statistical analysis; G. Howard and S. Ordway for editorial review; J. Carroll and C. Goodfellow for preparation of graphics; and D. McPherson for administrative assistance. The study was supported by US National Institutes of Health (NIH) grants AG011385, AG022074 and NS041787 to L.M., AG028233 to R.O.S.-M. and US NIH/National Center for Research Resources grant CO6RR018928 to the J. David Gladstone Institutes. Additional support was provided by the US Department of Agriculture Agricultural Research Service 5306-51530-016-00D to J.W.N. and from the NIH National Institute of Diabetes and Digestive and Kidney Diseases DK 054741 to J.V.B.

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R.O.S.-M. and L.M. developed the experimental design, performed data analysis and wrote the paper. R.O.S.-M. and J.W.N. carried out the lipidomics analysis. R.O.S.-M. performed the western blot and immunohistochemical analyses. G.-Q.Y. carried out the APP and Aβ measurements. R.O.S.-M., S.T. and K.S.-L. performed the behavioral testing and analyses. Y.Z. and L.G. provided primary neuronal cultures. I.H.C. provided oligomeric Aβ. J.J.P. and J.V.B. provided mice and contributed to experimental design. M.C. provided recombinant hAPP. R.O.S.-M. and B.H. carried out the electrophysiology experiments. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Rene O Sanchez-Mejia or Lennart Mucke.

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Lennart Mucke has a consulting agreement with Merck.

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Sanchez-Mejia, R., Newman, J., Toh, S. et al. Phospholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer's disease. Nat Neurosci 11, 1311–1318 (2008). https://doi.org/10.1038/nn.2213

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