Alzheimer's-associated Aβ oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal

Abstract

It now appears likely that soluble oligomers of amyloid-β 1-42 peptide, rather than insoluble fibrils, act as the primary neurotoxin in Alzheimer's disease (AD). Consequently, compounds capable of altering the assembly state of these oligomers (referred to as ADDLs) may have potential for AD therapeutics. Phenolic compounds are of particular interest for their ability to disrupt Aβ oligomerization and reduce pathogenicity. This study has focused on oleocanthal (OC), a naturallyoccurring phenolic compound found in extra-virgin olive oil. OC increased the immunoreactivity of soluble Aβ species, when assayed with both sequence-and conformation-specific Aβ antibodies, indicating changes in oligomer structure. Analysis of oligomers in the presence of OC showed an upward shift in MW and a ladder-like distribution of SDS-stable ADDL subspecies. In comparison with control ADDLs, oligomers formed in the presence of OC (Aβ-OC) showed equivalent colocalization at synapses but exhibited greater immunofluorescence as a result of increased antibody recognition. The enhanced signal at synapses was not due to increased synaptic binding, as direct detection of fluorescently-labeled ADDLs showed an overall reduction in ADDL signal in the presence of OC. Decreased binding to synapses was accompanied by significantly less synaptic deterioration assayed by drebrin loss. Additionally, treatment with OC improved antibody clearance of ADDLs. These results indicate oleocanthal is capable of altering the oligomerization state of ADDLs while protecting neurons from the synaptopathological effects of ADDLs and suggest OC as a lead compound for development in AD therapeutics.

Oleocanthal: A Naturally Occurring Anti-Inflammatory Agent in Virgin Olive Oil

“…Alzheimer's disease) and PHF6 enables the phosphorylation of tau, thus the convalent modification of PHF6 peptide disrupts tau-tau interaction and subsequent fibril formation (Li et al, 2009) (Figure 4). Β-amyloid peptides (Aβ) are another type of lesion that are characteristic of Alzheimer's disease (Guela et al, 1998), as Aβ derived diffusible ligands (ADDLs) are neurotoxic factors proposed to instigate the onset of Alzheimer's disease (Pitt et al, 2009). Pitt and colleagues (2009) demonstrated that in vitro, oleocanthal alters the structure of ADDLs and augments antibody clearance of ADDLs, therefore protecting hippocampal neurons from ADDL toxicity.…”

“…Further investigation demonstrated that oleocanthal inhibits inflammation in the same way as ibuprofen, and moreover, is substantially more potent on a equimolar basis (Beauchamp et al, 2005). Subsequent studies have shown that oleocanthal exhibits various modes of action in reducing inflammatoryrelated disease, including neuro-degenerative disease (Pitt et al, 2009, Li et al, 2009, jointdegenerative disease (Iacono et al, 2010) and specific cancers (Elnagar et al, 2011). Therefore, long term consumption of extra virgin olive oil (EVOO) containing oleocanthal may contribute to the health benefits associated with the Mediterranean dietary pattern.…”

Especiação de cobre e zinco em urina: importância dos metais em doenças neurodegenerativas

“…11 As formas mais frequentes de βA são constituídas por 40 e 42 aminoácidos. 9,[12][13][14] Os βA formados que assumem maior comprimento têm mais facilidade para uma rápida agregação, oligomerização e formação de fibrilas. 15 A forma de oligómero é a mais neurotóxica.…”

Efficacy of Oleuropein Aglycone in the Treatment of Transthyretin-Amyloidosis

“…OleA was more effective than Oleuropein and hydroxytyrosol (they are also effective but to a lesser extent) as inhibitor of Tau fibrillization [14]. OleA was also shown to modify Amyloid Precursor Protein-(APP) processing, increasing the formation of the non-amyloidogenic and neuroprotective sAPPα fragment and to decrease Aβ oligomers in HEK695 cell supernatants by increasing matrix metalloproteinase-9 (MMP-9) secretion [15]. These results are very promising and pave the way to a more extensive investigation on OleA ability to inhibit toxic amyloid aggregation of many other amyloid-associated peptides/proteins.…”