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

• Published in: Nature neuroscience Vol. 11; no. 5; pp. 547 - 554
• Main Authors: Berman, Diego E, Dall'Armi, Claudia, Voronov, Sergey V, McIntire, Laura Beth J, Zhang, Hong, Moore, Ann Z, Staniszewski, Agniezka, Arancio, Ottavio, Kim, Tae-Wan, Di Paolo, Gilbert
• Format: Journal Article
• Language: English
• Published: 01.05.2008
• ISSN: 1097-6256
• DOI: 10.1038/nn.2100

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