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

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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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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.).

Author information

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.

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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