THEoleacein andoleocanthal are two biophenols of quality extra virgin olive oil that can modulate inflammation, neurodegenerative diseases, including Alzheimer's (AD, Alzheimer disease), and cancer, actions demonstrated in studies on both cells and animals.
Oleacein (Olea) derives from oleuropein, while the oleocanthal (Oleo) from ligstroside, both contained in the olive, and belong to the family of secoiridoidi; both Oleo and Olea possess a “dialdehyde group” which makes these molecules very reactive.
It has also been shown that when these molecules are injected into experimental animals, they rapidly disappear; the same phenomenon occurs when they are added to cell culture media.
Pharmacokinetic studies have been difficult to study because the dialdehyde groups react readily with primary amines present in biological fluids (amino acids, proteins, peptides, polyamines, plasma…) and in the cultivation grounds of cells to form a tetrahydropyridine adduct (Schiff base) (1).
The question then arose as to whether the biological effects are linked to the dialdehyde molecules, i.e. the parent molecules, or to the molecules derived from the reaction with primary amines, both biogenic and non-biogenic.
The study by Daniel Di Risola et al. (2) has demonstrated that oleacein and oleocanthal react quickly with a primary, non-biogenic amine, used very frequently in the laboratory for its buffering effect [(tris (hydroxymethyl) aminomethane, acronym Tris)] forming Tris-Oleacein (Tris-Olea) and Tris-Oleocanthal (Tris-Oleo).
This study then demonstrated, with suitable substrates, that the reaction derivatives, i.e. Tris-Olea and Tris-Oleo, maintain their antioxidant and anti-inflammatory properties.
Previous studies have documented that in Alzheimer's disease, mutations in Tau proteins, or even their abnormal hyperphosphorylation, generate Tau filaments that can assemble together and form tangles typical of the disease.
The normal function of Tau proteins is to stabilize the intracellular microtubules of the cytoskeleton of nerve fibers and to further transport molecules from the neuron body to the synapse.
Furthermore, under physiological conditions, microtubules serve to expel toxic proteins from cells.
Tau hyperphosphorylation leads to a steric change in the protein, which changes from linear to pleated; at this stage, the sequence is essential for the formation of pathological aggregates, hence neurofibrillary tangles.
Oleocanthal inhibits tau fibril formation in tauopathies by modifying this hexapeptide 306-VQIXXK-311 (PHF-6). These six tau amino acids normally prevent fibril aggregation, but when hyperphosphorylated, they aggregate and damage neurons by forming amyloid plaques.
Hyperphosphorylation of the Tau protein causes a conformational change, transforming it from a linear (pencil-like) protein to a pleated (wavy-roof-like) protein.
Oleocanthal binds, with its dialdehyde moiety, to the epsilon-amino group of lysine to give the typical chemical reaction of secondary imines or “Schiff bases”, with the elimination of water molecules.
This reaction between Oleo and Tau protein was confirmed by matrix-assisted laser desorption ionization mass spectrometry analysis.
Molecular studies have shown that for its function, Oleo must have its two functional open-ring aldehyde groups.
This open ring conformation is what normally gives EVO oil its pungent taste sensation in the oropharynx, typical of some cultivar rich in biophenols.
In practice, Oleo, by binding to the hyperphosphorylated amino acid sequence of the Tau protein, inhibits the possibility of this protein binding to other Tau proteins to form a pleated structure.
In Alzheimer's disease, Oleo also increases, through the blood-brain barrier, the elimination from the brain of ADDL proteins (Amyloid beta Derived Diffusible Ligands) which are the cause of the hyperphosphorylation of Tau proteins.
Furthermore, oleocanthal prevents ADDL oligomerization (i.e. the formation of ADDL oligomer clusters which cause amyloid plaques)(3).
The study by Daniel Di Risola and colleagues confirms the hypothesis of Darakjian and colleagues on this link between the two secoiridoids and primary amines, at the same time opening a new interpretative framework for understanding the numerous evidences regarding the properties of Olea and Oleo “in vivo”.
Bibliography
- Lucy I. Darakjian et al. ACS Pharmacol. Transl. Sci. 2021, 4, 179–192.
- By Risola D. et al. Molecules 2025, 30(7), 1645; https://doi.org/10.3390/molecules30071645
- Vujovic A. Olive Oil: History and Science. 2020, Tozzuolo Editore, Perugia. Chapter 17.17 Neuroprotective Effects of EVO Biomolecules in the Prevention of Alzheimer's Disease. Pages 394-398
