Oligomeric amyloid-beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism.
Synaptic dysfunction caused by oligomeric assemblies of amyloid-beta peptide (Abeta) has been linked to cognitive deficits in Alzheimer's disease. Here we found that incubation of primary cortical neurons with oligomeric Abeta 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 Abeta 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 Abeta on hippocampal long-term potentiation was strongly suppressed in slices from Synj1+/- mice, suggesting that Abeta-induced synaptic dysfunction can be ameliorated by treatments that maintain the normal PtdIns(4,5)P2 balance in the brain.
Berman
Diego E
DE
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.
Dall'Armi
Claudia
C
Voronov
Sergey V
SV
McIntire
Laura Beth J
LB
Zhang
Hong
H
Moore
Ann Z
AZ
Staniszewski
Agniezka
A
Arancio
Ottavio
O
Kim
Tae-Wan
TW
Di Paolo
Gilbert
G
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D006579:Heterozygote; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008818:Mice, Neurologic Mutants; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009924:Organ Culture Techniques; D016716:PC12 Cells; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism; D051381:Rats; D010738:Type C Phospholipases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D009419:Nerve Tissue Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; C097702:synaptojanin; D010744:Phosphoric Monoester Hydrolases; D010738:Type C Phospholipases