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Introduction: Recent studies highlighted the role of olive polyphenols in disrupting the ordered structure of highly cytotoxic amyloid beta protofibrils and the efficacy of a derivatized form of glutathione to counteract neuronal oxidative stress affecting specific brain regions at early stages of Alzheimer's disease (AD) pathogenesis. We performed a randomized cross-over clinical trial to evaluate their potential benefits in mild AD., Methods: Oleuropein and S-acetyl glutathione were administered as dietary supplement for 6 months to 18 patients diagnosed for probable mild AD according to International Working Group 2 criteria. Patients underwent an extensive cognitive and behavioral neuropsychological test battery at the beginning and end of the study to evaluate cognitive deterioration, memory, visuospatial abilities, attention, language, executive functions, and behavioral disorders. We compared patients receiving treatment to patients receiving no treatment., Results: All the measured neurocognitive parameters stabilized or improved after the treatment in all patients., Discussion: Dietary supplement with olive polyphenols and bioavailable glutathione could be useful for patients diagnosed with mild AD., Competing Interests: Massimo Marianetti, Silvia Pinna, Angelo Venuti, and Gianfranco Liguri did not receive support for the submitted work nor receive any support outside the submitted work in the past 36 months. Massimo Marianetti, Silvia Pinna, and Angelo Venuti do not have any relationships/activities/interests to disclose. Gianfranco Liguri has been in the past 36 months a shareholder and unpaid scientific advisor for Innbiotec Pharma Srl, which developed the nutraceutical formulation and he has no other relationships/activities/interests to disclose. All the authors have nothing else to disclose according to the ICMJE Disclosure Form., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Oxidative stress has a prominent role in life-span regulation of living organisms. One of the endogenous free radical scavenger systems is associated with glutathione (GSH), the most abundant nonprotein thiol in mammalian cells, acting as a major reducing agent and in antioxidant defense by maintaining a tight control over redox status. We have recently designed a series of novel S-acyl-GSH derivatives capable of preventing amyloid oxidative stress and cholinergic dysfunction in Alzheimer disease models, upon an increase in GSH intake. In this study we show that the longevity of the wild-type N2 Caenorhabditis elegans strain was significantly enhanced by dietary supplementation with linolenoyl-SG (lin-SG) thioester with respect to the ethyl ester of GSH, linolenic acid, or vitamin E. RNA interference analysis and activity inhibition assay indicate that life-span extension was mediated by the upregulation of Sir-2.1, a NAD-dependent histone deacetylase ortholog of mammalian SIRT1. In particular, lin-SG-mediated overexpression of Sir-2.1 appears to be related to the Daf-16 (FoxO) pathway. Moreover, the lin-SG derivative protects N2 worms from the paralysis and oxidative stress induced by Aβ/H2O2 exposure. Overall, our findings put forward lin-SG thioester as an antioxidant supplement triggering sirtuin upregulation, thus opening new future perspectives for healthy aging or delayed onset of oxidative-related diseases., (Copyright © 2014 Elsevier Inc. All rights reserved.)

UV-induced toxicity is characterized by marked oxidative stress, accompanied by the depletion of key cellular antioxidants, particularly glutathione (GSH). Replenishing cellular GSH may represent a means of counteracting UV-induced toxicity: however, treatment with free GSH is not therapeutically effective due to its unfavorable pharmacokinetic properties. In this study, we show that S-acyl-glutathione (acyl-SG) derivatives, which consist of an acyl chain (of variable length and saturation) linked via a thioester bond to GSH, increase intracellular levels of reduced GSH in primary skin fibroblasts, adenocarcinoma HeLa and neuroblastoma SH-SY5Y cells. Consistent with this, acyl-SG derivatives protect against UV-induced reactive oxygen species (ROS) production and UV-B/C-mediated lipid peroxidation and caspase-3 activation in the analyzed cell lines, with unsaturated thioesters displaying a significantly greater protective effect. Taken together, our findings suggest that acyl-SG thioesters may be therapeutically effective in the treatment of UV-related skin disorders and oxidative stress-mediated conditions in general., (© 2012 Wiley Periodicals, Inc. Photochemistry and Photobiology © 2012 The American Society of Photobiology.)

Oxidative stress-mediated neuronal death may be initiated by a decrease in glutathione (GSH), whose levels are reduced in mitochondrial and synaptosomal fractions of specific CNS regions in Alzheimer disease (AD) patients. Currently, the use of GSH as a therapeutic agent is limited by its unfavorable pharmacokinetic properties. In this study, we designed the synthesis of new S-acyl glutathione (acyl-SG) thioesters of fatty acids via N-acyl benzotriazole-intermediate production and investigated their potential for targeted delivery of the parent GSH and free fatty acid to amyloid-exposed fibroblasts from familial AD patients and human SH-SY5Y neuroblastoma cells. Cell culture supplementation with acyl-SG derivatives triggers a significant decrease in lipid peroxidation and mitochondrial dysfunction in a fatty acid unsaturation degree-dependent fashion. Acyl-SG thioesters also protect cholinergic neurons against Aβ-induced damage and reduce glial reaction in rat brains. Collectively, these findings suggest that acyl-SG thioesters could prove useful as a tool for controlling AD-induced cerebral deterioration., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Peptides and proteins can convert from their soluble forms into highly ordered fibrillar aggregates, giving rise to pathological conditions ranging from neurodegenerative disorders to systemic amyloidoses. It is increasingly recognized that protein oligomers forming early in the process of fibril aggregation represent the pathogenic species in protein deposition diseases. The N-terminal domain of the HypF protein from Escherichia coli (HypF-N) has previously been shown to form, under distinct conditions, two types of HypF-N oligomers with indistinguishable morphologies but distinct structural features at the molecular level. Only the oligomer type exposing hydrophobic surfaces and possessing sufficient structural plasticity is toxic (type A), whereas the other type is benign to cultured cells (type B). Here we show that only type A oligomers are able to induce a Ca(2+) influx from the cell medium to the cytosol, to penetrate the plasma membrane, to increase intracellular reactive oxygen species production, lipid peroxidation and release of intracellular calcein, resulting in the activation of the apoptotic pathway. Remarkably, these oligomers can also induce a loss of cholinergic neurons when injected into rat brains. By contrast, markers of cellular stress and viability were unaffected in cultured and rat neuronal cells exposed to type B oligomers. The analysis of the time scales of such effects indicates that the difference of toxicity between the two oligomer types involve the early events of the toxicity cascade, shedding new light on the mechanism of action of protein oligomers and on the molecular targets for the therapeutic intervention against protein deposition diseases., (© 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.)

A growing body of evidence implicates low membrane cholesterol in the pathogenesis of Alzheimer's disease (AD). Here we show that Aβ42 soluble oligomers accumulate more slowly and in reduced amount at the plasma membranes of PS-1L392V and APPV717I fibroblasts from familial AD (FAD) patients enriched in cholesterol content than at the counterpart membranes. The Aβ42-induced production of reactive oxygen species (ROS) and the increase in membrane lipoperoxidation were also prevented by high membrane cholesterol, thus resulting in a higher resistance to amyloid toxicity with respect to control fibroblasts. On the other hand, the recruitment of amyloid assemblies to the plasma membrane of cholesterol-depleted fibroblasts was significantly increased, thus triggering an earlier and sharper production of ROS and a higher membrane oxidative injury. These results identify membrane cholesterol as being key to Aβ42 oligomer accumulation at the cell surfaces and to the following Aβ42-induced cell death in AD neurons., (Copyright © 2009 Elsevier Inc. All rights reserved.)

Increasing evidence indicates that cell surfaces are early interaction sites for Abeta-derived diffusible ligands (ADDLs) and neurons in Alzheimer's disease (AD) pathogenesis. Our previous data showed significant oxidative damage at the plasma membrane in fibroblasts from familial AD patients with enhanced Abeta production. Here, we report that lipid rafts, ordered membrane microdomains, are chronic mediators of Abeta-induced lipid peroxidation in SH-SY5Y human neuroblastoma cells overexpressing amyloid precursor protein (APPwt) and APPV717G genes and in fibroblasts bearing the APPV717I gene mutation. Confocal microscope analysis showed that Abeta-oxidised rafts recruit more ADDLs than corresponding domains in control cells, triggering a further increase in membrane lipid peroxidation and loss of membrane integrity. Moreover, amyloid pickup at the oxidative-damaged domains was prevented by enhanced cholesterol levels, anti-ganglioside (GM1) antibodies, the B subunit of cholera toxin and lipid raft structure alteration. An enhanced structural rigidity of the detergent-resistant domains, isolated from APPwt and APPV717G cells and exposed to ADDLs, indicates a specific perturbation of raft physicochemical features in cells facing increased amyloid assembly at the membrane surface. These data identify lipid rafts as key mediators of oxidative damage as a result of their ability to recruit aggregates to the cell surface.