The deficit in long-term potentiation induced by chronic administration of amyloid-beta is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025.
Amyloid-beta (Abeta) peptides, the primary component of the amyloid plaques in Alzheimer's disease (AD), exert profound effects on neurons in vitro and negatively impact on neuronal function in vivo. One of the consequences of increased Abeta in the brain, either as a result of overexpression of the precursor amyloid precursor protein in transgenic mice, or injection into the brain is a decrease in one form of synaptic plasticity, long-term potentiation (LTP) in the hippocampus. Here we investigated the effect of infusion of Abeta for 28 days on LTP in dentate gyrus of rats and demonstrate that it was profoundly decreased compared with control-treated rats. We show that this effect is accompanied by increased activity of caspase 3, which is an indicator of cell stress. Significantly these changes were attenuated in animals which were pretreated with particles incorporating phosphatidylglycerol (VP025) and the evidence indicated that even when treatment was given 2 weeks after the start of the Abeta infusion, VP025 was capable of attenuating Abeta-induced changes. The evidence suggests that activation of caspase 3 was mediated by an Abeta-induced increase in sphingomyelinase, with the subsequent production of ceramide which is known to have a detrimental effect on neuronal function.
Miller
Anne-Marie
AM
Trinity College Institute of Neuroscience, Physiology Department, Trinity College, Dublin 2, Ireland. milleram@tcd.ie
Piazza
Alessia
A
Martin
Darren S D
DS
Walsh
Michelle
M
Mandel
Arkady
A
Bolton
Anthony E
AE
Lynch
Marina A
MA
D016229:Amyloid beta-Peptides / Q000008:administration & dosage* / Q000378:metabolism; D000818:Animals; D053148:Caspase 3 / Q000187:drug effects* / Q000378:metabolism; D004558:Electric Stimulation; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects* / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D016229:Amyloid beta-Peptides; D053148:Caspase 3