Oleuropein Aglycone Protects Transgenic C. elegans Strains Expressing Aβ42 by Reducing Plaque Load and Motor Deficit

Abstract

The presence of amyloid aggregates of the 42 amino acid peptide of amyloid beta (Aβ42) in the brain is the characteristic feature of Alzheimer’s disease (AD). Amyloid beta (Aβ deposition is also found in muscle fibers of individuals affected by inclusion body myositis (sIBM), a rare muscular degenerative disease affecting people over 50. Both conditions are presently lacking an effective therapeutic treatment. There is increasing evidence to suggest that natural polyphenols may prevent the formation of toxic amyloid aggregates; this applies also to oleuropein aglycone (OLE), the most abundant polyphenol in extra virgin olive oil, previously shown to hinder amylin and Aβ aggregation. Here we evaluated the ability of OLE to interfere with Aβ proteotoxicity in vivo by using the transgenic CL2006 and CL4176 strains of Caenorhabditis elegans, simplified models of AD and of sIBM, which express human Aβ in the cytoplasm of body wall muscle cells. OLE-fed CL2006 worms displayed reduced Aβ plaque deposition, less abundant toxic Aβ oligomers, remarkably decreased paralysis and increased lifespan with respect to untreated animals. A protective effect was also observed in CL4176 worms but only when OLE was administered before the induction of the Aβ transgene expression. These effects were specific, dose-related, and not mediated by the known polyphenolic anti-oxidant activity, suggesting that, in this model organism, OLE interferes with the Aβ aggregation skipping the appearance of toxic species, as already shown in vitro for Aβ42.

18α-Glycyrrhetinic Acid Proteasome Activator Decelerates Aging and Alzheimer's Disease Progression inCaenorhabditiselegansand Neuronal Cultures

“…Likewise, a proteasome-dependent antiamyloidogenic activity has been attributed to resveratrol (39,51), ganoderic acid DM (6), thioflavin-T (2), and rolipram (42). Oleuropein aglycone was found to delay paralysis through Ab deposit reduction in an AD nematode model (19) and to exert antiaggregation and neuroprotective activity in an AD mouse model (24) and in rats coinjected with Ab 42 (24). production in DMSO-treated animals set to 100%, tetracycline was used as positive control for antioxidant activity), (C) catalase activity (mean value of catalase activity in DMSO-treated animals set to 1), and (D) real-time polymerase chain reaction analysis of gst-4, gcs-1, pbs-1, pbs-2, and pbs-5 genes (expression levels of each gene were arbitrarily set to 1 in DMSO-treated animals, pmp-3 gene expression was used as normalizer) in wt animals treated with 20 lg/ml 18a-GA or DMSO.…”

Natural Phenolic Compounds as Therapeutic and Preventive Agents for Cerebral Amyloidosis

“…Details of the studies were described in the reference (Ono et al 2012) extracts (Vepsäläinen et al 2013), pomegranate juice containing high levels of polyphenols (Hartman et al 2006), and a natural diet rich in polyphenols and polyunsaturated fatty acids (LMN diet) (Fernández-Fernández et al 2012). Other models include an A"-infused rat AD model treated with Cur (Hoppe et al 2013), and a transgenic Caenohabditis elegans model of A" amyloidosis treated with quercetin (Regitz et al 2014) and oleuropein (Diomede et al 2013;Grossi et al 2014). Furthermore, attenuation of neuropathology was reported in a tau transgenic mouse model of tauopathy treated with GSPE SantaMaria et al 2012).…”

Olive Oil Phenols as Promising Multi-targeting Agents Against Alzheimer’s Disease

“…In fact, OLE does not significantly reduce either lipid peroxidation in the cortex of TgCRND8 mice (Grossi et al 2013), nor intracellular superoxide level in the transgenic CL2600 C. elegans strain (Diomede et al 2013). Rather, OLE acts both as an inhibitor of amyloidogenic peptide aggregation (possibly through direct binding, as suggested by the previously cited MS and NMR studies) and as a signaling molecule promoting cellular protective responses like autophagy stimulation and inflammation reduction.…”

“…OLE has until now given more unequivocal positive results than OLC with regards to the inhibition of toxic amyloid aggregation and the stimulation of cellular protective mechanisms like autophagy. Moreover, the specificity and selectivity of OLC crosslinking activity still Rigacci et al (2011), Diomede et al (2013), Luccarini et al (2014), and Grossi et al (2013) Improvement in survival, cognitive function and motor performance in AD transgenic models (C. elegans, mouse) Diomede et al (2013) and Grossi et al (2013Grossi et al ( , 2014 Inflammation reduction Luccarini et al (2014), Grossi et al (2013Grossi et al ( , 2014, Dell'Agli et al (2010), Scoditti et al (2012), Sindona et al (2012), and Impellizzeri et al (2011) Autophagy activation Grossi et al (2013Grossi et al ( , 2014 Stimulation of hippocampal neurogenesis and increase in dopaminergic neurons Grossi et al (2014) and Sarbishegi et al (2014) Inhibition of tau aggregation Daccache et al (2011) Promotion of sAPP' fragment production Kostomoiri et al (2013) Antioxidant enzymes Inflammation reduction Beauchamp et al (2005) and Iacono et al (2010) needs to be confirmed in vivo, to exclude negative side effects on functional proteins. Nevertheless, the potent anti-inflammatory activity of OLC and its ability to promote A" degradation and clearance are valuable properties.…”

“…In fact, administration of OLE to the CL2600 Caenorhabditis elegans (C. elegans) strain, constitutively expressing A"(3-42), resulted in significantly lower plaque deposition and toxic oligomer formation, with a reduction in the extent of worm paralysis and an increase in survival (Diomede et al 2013). When A"(1-42) was aggregated in the presence of OLE and then injected in the nucleus basalis magnocellularis of adult male Wistar rats, it was not toxic to cholinergic neurons and did not raise an inflammatory reaction.…”