The deficit in long-term potentiation induced by chronic administration of amyloid-β is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025

Abstract

, et al.. The deficit in long-term potentiation induced by chronic administration of amyloid-β-is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025. Experimental Gerontology, Elsevier, 2009, 44 (4), pp.300. <10.1016/j.exger.2008.12.001>. <hal-00493095> Accepted ManuscriptThe deficit in long-term potentiation induced by chronic administration of amyloid-β-is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. ACCEPTED MANUSCRIPTThe deficit in long-term potentiation induced by chronic administration of amyloid--is attenuated by treatment of rats with a novel phospholipid-based drug formulation, VP025 ACCEPTED MANUSCRIPT ABSTRACTAmyloid-(A ) 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 A 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 A 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 A infusion, VP025 was capable of attenuating A -induced changes. The evidence suggests that activation of caspase 3 was mediated by an A -induced increase in sphingomyelinase, with the subsequent production of ceramide which is known to have a detrimental effect on neuronal function.

Neurotoxicity and Memory Deficits Induced by Soluble Low-Molecular-Weight Amyloid- 1-42 Oligomers Are Revealed In Vivo by Using a Novel Animal Model

“…Some of these studies have observed memory impairment following single brain infusion (Lesné et al, 2006;Shankar et al, 2008), but the toxicity of small A␤ 1-42 oligomers in vivo still needs to be established. The A␤ toxicity could not be determined using an osmotic pump system for prolonged administration of more mature A␤ species, which dynamically continues to oligomerize during this time and may stick into the pump (Malm et al, 2006;Miller et al, 2009;Ji et al, 2011). Other reports have shown that transgenic models overexpressing A␤ develop early synaptic alterations but lack the extensive cell death seen at the onset of memory decline in AD (Irizarry et al, 1997;Chishti et al, 2001;Oddo et al, 2003).…”

Application of Nanodiagnostics and Nanotherapy to CNS Diseases

“…In another finding, PEG and anti-Aβ Abs-coated CNPs (Aβ-CNPs-PEG) protected against oxidative stress/Aβ-mediated neurodegeneration through the brain-derived neurotrophic factor (BDNF) signaling pathway [56]. Another study found that anti-inflammatory phosphatidylglycerol-based phospholipid NPs (VP025) attenuated Aβ-induced long-term potentiation deficits by inhibiting caspase-3 activation [57]. Recent efforts have focused on exploiting NPs as drug carriers into the brain.…”

Alzheimer's Disease: Status of Low‐Dimensional Nanotherapeutic Materials

“…[202] Apart from the above NPs, the anti-inflammatory phosphatidylglycerol phospholipid nanoparticles (VP025) can also memorably inhibit the activation of caspase-3 in the hippocampus to improve the memory impairment of AD. [203] Lipid nanoparticles can be administered by intraperitoneal injection, which is very convenient. Such a relatively small size of nanoparticles meets with the absorption of drugs required so as not to jam the lungs and other organs, leading to animal deaths.…”