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Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism

Abstract

Synaptic dysfunction caused by oligomeric assemblies of amyloid-β peptide (Aβ) has been linked to cognitive deficits in Alzheimer's disease. Here we found that incubation of primary cortical neurons with oligomeric Aβ decreases the level of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), a phospholipid that regulates key aspects of neuronal function. The destabilizing effect of Aβ on PtdIns(4,5)P2 metabolism was Ca2+-dependent and was not observed in neurons that were derived from mice that are haploinsufficient for Synj1. This gene encodes synaptojanin 1, the main PtdIns(4,5)P2 phosphatase in the brain and at the synapses. We also found that the inhibitory effect of Aβ on hippocampal long-term potentiation was strongly suppressed in slices from Synj1+/− mice, suggesting that Aβ-induced synaptic dysfunction can be ameliorated by treatments that maintain the normal PtdIns(4,5)P2 balance in the brain.

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Figure 1: Oligomeric Aβ42 peptide causes a decrease in the levels of PtdIns(4,5)P2.
Figure 2: Oligomers of Aβ are potent destabilizers of PtdIns(4,5)P2.
Figure 3: oAβ42-triggered PtdIns(4,5)P2 deficits are calcium and NMDA receptor dependent.
Figure 4: Analysis of fluorescent PtdIns(4,5)P2 and DAG probes after treatment with oAβ42 in PC12 cells.
Figure 5: Hippocampi from mice lacking one copy of Synj1 show normal LTP in the presence of oAβ42.

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References

  1. Tanzi, R.E. & Bertram, L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120, 545–555 (2005).

    Article  CAS  Google Scholar 

  2. Haass, C. & Selkoe, D.J. Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid-β peptide. Nat. Rev. Mol. Cell Biol. 8, 101–112 (2007).

    Article  CAS  Google Scholar 

  3. Marjaux, E., Hartmann, D. & De Strooper, B. Presenilins in memory, Alzheimer's disease and therapy. Neuron 42, 189–192 (2004).

    Article  CAS  Google Scholar 

  4. Selkoe, D.J. Alzheimer's disease is a synaptic failure. Science 298, 789–791 (2002).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. Demuro, A. et al. Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J. Biol. Chem. 280, 17294–17300 (2005).

    Article  CAS  Google Scholar 

  8. Kayed, R. et al. Permeabilization of lipid bilayers is a common conformation-dependent activity of soluble amyloid oligomers in protein misfolding diseases. J. Biol. Chem. 279, 46363–46366 (2004).

    Article  CAS  Google Scholar 

  9. Sokolov, Y. et al. Soluble amyloid oligomers increase bilayer conductance by altering dielectric structure. J. Gen. Physiol. 128, 637–647 (2006).

    Article  CAS  Google Scholar 

  10. Arispe, N., Diaz, J.C. & Simakova, O. Aβ ion channels. Prospects for treating Alzheimer's disease with Aβ channel blockers. Biochim. Biophys. Acta 1768, 1952–1965 (2007).

    Article  CAS  Google Scholar 

  11. Wang, H.Y., Lee, D.H., Davis, C.B. & Shank, R.P. Amyloid peptide Aβ (1–42) binds selectively and with picomolar affinity to α7 nicotinic acetylcholine receptors. J. Neurochem. 75, 1155–1161 (2000).

    Article  CAS  Google Scholar 

  12. Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651–657 (2006).

    Article  CAS  Google Scholar 

  13. Yin, H.L. & Janmey, P.A. Phosphoinositide regulation of the actin cytoskeleton. Annu. Rev. Physiol. 65, 761–789 (2003).

    Article  CAS  Google Scholar 

  14. Suh, B.C. & Hille, B. Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate. Curr. Opin. Neurobiol. 15, 370–378 (2005).

    Article  CAS  Google Scholar 

  15. Hilgemann, D.W., Feng, S. & Nasuhoglu, C. The complex and intriguing lives of PIP2 with ion channels and transporters. Sci. STKE 2001, RE19 (2001).

    CAS  PubMed  Google Scholar 

  16. Stokes, C.E. & Hawthorne, J.N. Reduced phosphoinositide concentrations in anterior temporal cortex of Alzheimer-diseased brains. J. Neurochem. 48, 1018–1021 (1987).

    Article  CAS  Google Scholar 

  17. Landman, N. et al. Presenilin mutations linked to familial Alzheimer's disease cause an imbalance in phosphatidylinositol 4,5-bisphosphate metabolism. Proc. Natl. Acad. Sci. USA 103, 19524–19529 (2006).

    Article  CAS  Google Scholar 

  18. Nasuhoglu, C. et al. Nonradioactive analysis of phosphatidylinositides and other anionic phospholipids by anion-exchange high-performance liquid chromatography with suppressed conductivity detection. Anal. Biochem. 301, 243–254 (2002).

    Article  CAS  Google Scholar 

  19. Townsend, M. et al. Orally available compound prevents deficits in memory caused by the Alzheimer amyloid-β oligomers. Ann. Neurol. 60, 668–676 (2006).

    Article  CAS  Google Scholar 

  20. McLaurin, J., Golomb, R., Jurewicz, A., Antel, J.P. & Fraser, P.E. Inositol stereoisomers stabilize an oligomeric aggregate of Alzheimer amyloid β peptide and inhibit abeta -induced toxicity. J. Biol. Chem. 275, 18495–18502 (2000).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. Hsiao, K. et al. Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice. Science 274, 99–102 (1996).

    Article  CAS  Google Scholar 

  23. Townsend, M., Shankar, G.M., Mehta, T., Walsh, D.M. & Selkoe, D.J. Effects of secreted oligomers of amyloid-β protein on hippocampal synaptic plasticity: a potent role for trimers. J. Physiol. (Lond.) 572, 477–492 (2006).

    Article  CAS  Google Scholar 

  24. De Felice, F.G. et al. Aβ oligomers induce neuronal oxidative stress through an N-methyl-d-aspartate receptor–dependent mechanism that is blocked by the Alzheimer drug memantine. J. Biol. Chem. 282, 11590–11601 (2007).

    Article  CAS  Google Scholar 

  25. Hurley, J.H. & Meyer, T. Subcellular targeting by membrane lipids. Curr. Opin. Cell Biol. 13, 146–152 (2001).

    Article  CAS  Google Scholar 

  26. Cremona, O. et al. Essential role of phosphoinositide metabolism in synaptic vesicle recycling. Cell 99, 179–188 (1999).

    Article  CAS  Google Scholar 

  27. Walsh, D.M. et al. Naturally secreted oligomers of amyloid-β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

    Article  CAS  Google Scholar 

  28. Walsh, D.M. & Selkoe, D.J. Aβ oligomers—a decade of discovery. J. Neurochem. 101, 1172–1184 (2007).

    Article  CAS  Google Scholar 

  29. Gong, B. et al. Ubiquitin hydrolase Uch-L1 rescues β-amyloid–induced decreases in synaptic function and contextual memory. Cell 126, 775–788 (2006).

    Article  CAS  Google Scholar 

  30. Kim, W.T. et al. Delayed reentry of recycling vesicles into the fusion-competent synaptic vesicle pool in synaptojanin 1 knockout mice. Proc. Natl. Acad. Sci. USA 99, 17143–17148 (2002).

    Article  CAS  Google Scholar 

  31. Mani, M. et al. The dual phosphatase activity of synaptojanin1 is required for both efficient synaptic vesicle endocytosis and reavailability at nerve terminals. Neuron 56, 1004–1018 (2007).

    Article  CAS  Google Scholar 

  32. Irie, F., Okuno, M., Pasquale, E.B. & Yamaguchi, Y. EphrinB-EphB signaling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1. Nat. Cell Biol. 7, 501–509 (2005).

    Article  CAS  Google Scholar 

  33. Lambert, M.P. et al. Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins. Proc. Natl. Acad. Sci. USA 95, 6448–6453 (1998).

    Article  CAS  Google Scholar 

  34. Klyubin, I. et al. Amyloid beta protein immunotherapy neutralizes Aβ oligomers that disrupt synaptic plasticity in vivo. Nat. Med. 11, 556–561 (2005).

    Article  CAS  Google Scholar 

  35. Kim, J.H., Anwyl, R., Suh, Y.H., Djamgoz, M.B. & Rowan, M.J. Use-dependent effects of amyloidogenic fragments of (β)-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo. J. Neurosci. 21, 1327–1333 (2001).

    Article  CAS  Google Scholar 

  36. Maloney, M.T. & Bamburg, J.R. Cofilin-mediated neurodegeneration in Alzheimer's disease and other amyloidopathies. Mol. Neurobiol. 35, 21–44 (2007).

    Article  CAS  Google Scholar 

  37. Marks, B. & McMahon, H.T. Calcium triggers calcineurin-dependent synaptic vesicle recycling in mammalian nerve terminals. Curr. Biol. 8, 740–749 (1998).

    Article  CAS  Google Scholar 

  38. Bauerfeind, R., Takei, K. & De Camilli, P. Amphiphysin I is associated with coated endocytic intermediates and undergoes stimulation-dependent dephosphorylation in nerve terminals. J. Biol. Chem. 272, 30984–30992 (1997).

    Article  CAS  Google Scholar 

  39. Lee, S.Y., Wenk, M.R., Kim, Y., Nairn, A.C. & De Camilli, P. Regulation of synaptojanin 1 by cyclin-dependent kinase 5 at synapses. Proc. Natl. Acad. Sci. USA 101, 546–551 (2004).

    Article  CAS  Google Scholar 

  40. Mulkey, R.M., Endo, S., Shenolikar, S. & Malenka, R.C. Involvement of a calcineurin/inhibitor-1 phosphatase cascade in hippocampal long-term depression. Nature 369, 486–488 (1994).

    Article  CAS  Google Scholar 

  41. Lott, I.T. & Head, E. Down syndrome and Alzheimer's disease: a link between development and aging. Ment. Retard. Dev. Disabil. Res. Rev. 7, 172–178 (2001).

    Article  CAS  Google Scholar 

  42. Greene, L.A. & Tischler, A.S. Establishment of a noradrenergic clonal line of rat adrenal pheochromocytoma cells which respond to nerve growth factor. Proc. Natl. Acad. Sci. USA 73, 2424–2428 (1976).

    Article  CAS  Google Scholar 

  43. Banker, G.A. & Goslin, K. Culturing Nerve Cells (MIT Press, Cambridge, Massachusetts, 1991).

    Google Scholar 

  44. Dahlgren, K.N. et al. Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability. J. Biol. Chem. 277, 32046–32053 (2002).

    Article  CAS  Google Scholar 

  45. Thinakaran, G., Teplow, D.B., Siman, R., Greenberg, B. & Sisodia, S.S. Metabolism of the “Swedish” amyloid precursor protein variant in neuro2a (N2a) cells. Evidence that cleavage at the “β-secretase” site occurs in the golgi apparatus. J. Biol. Chem. 271, 9390–9397 (1996).

    Article  CAS  Google Scholar 

  46. Puzzo, D. et al. Amyloid-β peptide inhibits activation of the nitric oxide/cGMP/cAMP-responsive element-binding protein pathway during hippocampal synaptic plasticity. J. Neurosci. 25, 6887–6897 (2005).

    Article  CAS  Google Scholar 

  47. Morris, R.G. Synaptic plasticity and learning: selective impairment of learning rats and blockade of long-term potentiation in vivo by the N-methyl-d-aspartate receptor antagonist AP5. J. Neurosci. 9, 3040–3057 (1989).

    Article  CAS  Google Scholar 

  48. Gong, B. et al. Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J. Clin. Invest. 114, 1624–1634 (2004).

    Article  CAS  Google Scholar 

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Acknowledgements

We would like to thank P. De Camilli and O. Cremona for providing the Synj1 mutant mice, K. Hsiao-Ashe for providing the App mutant mice, D. Selkoe for the gift of CHO APP(7WD4) cells, E. Micevska for technical help with the animals and the genotyping, P. Scheiffele, P. De Camilli, M. Wenk, A. Bhalla and B. Chang for critical reading of the manuscript and G. Thinakaran (University of Chicago) for providing the stable N2a cell line. This work was supported by grants from the US National Institute of Neurological Diseases and Stroke (NS043467 to T.-W.K., NS056049 to G.D.P. and NS049442 to O.A.), the US National Institute of Child Health and Human Development (HD047733 to G.D.P), the US National Center for Complementary and Alternative Medicine (AT002643 to T.-W.K.), SMART Biosciences (G.D.P.) and the Cure Alzheimer's Fund (T.-W.K.).

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D.E.B. designed, coordinated and carried out the bulk of experiments, and contributed to the writing of the manuscript. C.D. performed the fluorescent PtdIns(4,5)P2/DAG probe experiments and image analysis. S.V.V. carried out the Western blot analysis, lipid measurements in Synj1+/− neurons and ATP measurements. H.Z. and O.A. contributed the electrophysiology experiments. L.B.J.M. and A.Z.M. prepared and analyzed synthetic and cell-derived Aβ species. A.S. and O.A. contributed the behavioral experiments. T.-W.K. and G.D.P. conceived and supervised the project, wrote the manuscript and contributed equally to this work.

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Correspondence to Tae-Wan Kim or Gilbert Di Paolo.

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Tae-Wan Kim is a shareholder and consultant of SMART Biosciences, Inc.

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Berman, D., Dall'Armi, C., Voronov, S. et al. Oligomeric amyloid-β peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nat Neurosci 11, 547–554 (2008). https://doi.org/10.1038/nn.2100

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