Article abstract
Nature Neuroscience 11, 547 - 554 (2008)
Published online: 6 April 2008 | doi:10.1038/nn.2100
Oligomeric amyloid-
peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism
Diego E Berman1, Claudia Dall'Armi1, Sergey V Voronov1, Laura Beth J McIntire1, Hong Zhang1, Ann Z Moore1, Agniezka Staniszewski1, Ottavio Arancio1, Tae-Wan Kim1 & Gilbert Di Paolo1
Abstract
Synaptic dysfunction caused by oligomeric assemblies of amyloid-
peptide (A) has been linked to cognitive deficits in Alzheimer's disease. Here we found that incubation of primary cortical neurons with oligomeric A 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 A 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 A on hippocampal long-term potentiation was strongly suppressed in slices from Synj1+/-
mice, suggesting that A-induced synaptic dysfunction can be ameliorated by treatments that maintain the normal PtdIns(4,5)P2 balance in the brain.
- Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032, USA.
Correspondence to: Tae-Wan Kim1 e-mail: twk16@columbia.edu
Correspondence to: Gilbert Di Paolo1 e-mail: gil.dipaolo@columbia.edu
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