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