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

Synaptic dysfunction caused by oligomeric assemblies of amyloid-beta peptide (A beta) has been linked to cognitive deficits in Alzheimer's disease. Here we found that incubation of primary cortical neurons with oligomeric A beta decreases the level of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P-2), a phospholipid that regulates key aspects of neuronal function. The destabilizing effect of A beta on PtdIns(4,5)P-2 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)P-2 phosphatase in the brain and at the synapses. We also found that the inhibitory effect of A beta on hippocampal long-term potentiation was strongly suppressed in slices from Synj1(+/-) mice, suggesting that A beta-induced synaptic dysfunction can be ameliorated by treatments that maintain the normal PtdIns(4,5)P-2 balance in the brain.