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22 February 2023

Molecular Mechanisms of the Protective Effects of Olive Leaf Polyphenols against Alzheimer’s Disease

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1
Department of Physiology, Institute of Nutrition and Food Technology “José Mataix Verdú”, Biomedical Research Centre, University of Granada, 18016 Armilla, Spain
2
Research and Development Functional Food Centre (CIDAF), Health Science Technological Park, Avenida del Conocimiento 37, 18016 Granada, Spain
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Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
4
Center for Human Nutrition and Mediterranean Foods (NUTREA), University of Catania, 95123 Catania, Italy
Int. J. Mol. Sci.2023, 24(5), 4353;https://doi.org/10.3390/ijms24054353
This article belongs to the Special Issue Bioactive Compounds from Agrifood Byproducts: Their Use in Medicine and Biology
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Abstract

Alzheimer’s Disease (AD) is the cause of around 60–70% of global cases of dementia and approximately 50 million people have been reported to suffer this disease worldwide. The leaves of olive trees (Olea europaea) are the most abundant by-products of the olive grove industry. These by-products have been highlighted due to the wide variety of bioactive compounds such as oleuropein (OLE) and hydroxytyrosol (HT) with demonstrated medicinal properties to fight AD. In particular, the olive leaf (OL), OLE, and HT reduced not only amyloid-β formation but also neurofibrillary tangles formation through amyloid protein precursor processing modulation. Although the isolated olive phytochemicals exerted lower cholinesterase inhibitory activity, OL demonstrated high inhibitory activity in the cholinergic tests evaluated. The mechanisms underlying these protective effects may be associated with decreased neuroinflammation and oxidative stress via NF-κB and Nrf2 modulation, respectively. Despite the limited research, evidence indicates that OL consumption promotes autophagy and restores loss of proteostasis, which was reflected in lower toxic protein aggregation in AD models. Therefore, olive phytochemicals may be a promising tool as an adjuvant in the treatment of AD.

1. Introduction

Alzheimer’s Disease (AD) is the cause of around 60–70% of global cases of dementia [1] and approximately 50 million people have been reported to suffer from this disease worldwide [2]. In fact, AD incidence rates double every 5 years from 60 years of age [3] and it is estimated that dementia will affect 81.1 million people worldwide in 2040 [2,4].
The etiopathogenesis of AD is characterized by two histopathological events: the senile plaque aggregation formed by amyloid-β peptides (Aβ) in the central nervous system and the formation of neurofibrillary tangles (NFTs) associated with the accumulation of Tau protein in the hippocampus, neocortical area, and amygdala [4]. These events are associated with an increase in mitochondrial dysfunction, oxidative stress, glucose homeostasis alteration in the brain, neuroinflammation, and disturbances in the proteostatic network, which favor the appearance of senile plaques and NFTs, generating atrophy and neuron death characteristic of AD [5].
AD is a multifactorial disease whose appearance and development are marked by the interaction between genetic predisposition and external factors throughout life [4]. Among the risk factors, aging, gender (higher incidence in women), alcohol and tobacco consumption, obesity, and metabolic disorders such as diabetes mellitus, as well as a low cultural level and family history, have been highlighted [1]. Some of these risk factors, including physical activity, diet, smoking, and alcoholism, could be modified in order to reduce the onset of the disease [4].
Although there is still no pharmacological therapy for its treatment, the preventive and/or therapeutic nutritional interventions against AD have been gaining prominence in recent years [1]. It is known that 35% of dementias could be caused by modifiable risk factors associated with lifestyle, including the type of diet [1]. In particular, the Mediterranean Diet (MD), characterized by a high consumption of legumes, vegetables, fruits, vitamins, and virgin olive oil, and a low consumption of red meat, has been shown to reduce the incidence of AD [1]. MD presents a high contribution of bioactive substances such as phenolic compounds, which have been shown to exert a protective effect in AD [6]. In particular, the intake of phytochemical compounds naturally present in foods, such as oleuropein (OLE), hydroxytyrosol (HT), luteolin (LU), catechin, and curcumin, are related to neuroprotective effects in AD through the modulation of mechanisms such as oxidative stress and neuroinflammation, besides reducing the deposition and toxicity of the misfolded proteins involved [7,8,9,10,11,12].
The leaves of the olive tree (Olea europaea) are the most abundant by-product in the olive grove industry. In Spain, between 1 and 5 tons of waste are generated per hectare in the form of branches and leaves. OLs are long, hard, and lanceolate, and their edges curl up due to desiccation [13]. It is possible to obtain olive leaf extracts enriched in certain compounds after grinding and processing them with an extraction solvent such as methanol, ethanol, or water, or a mixture thereof. In addition, separation or concentration procedures can be applied to enrich extracts in particular molecules [14]. OLs have excellent medicinal properties thanks to the wide variety of bioactive compounds present in them. In this review, the preventive and therapeutic effect of olive compounds against AD were reviewed from the point of view of the molecular mechanisms involved.

2. Phytochemical Characterization of Olive Leaves

OLs are consumed worldwide as a nutraceutical product due to their numerous and demonstrated health properties. In fact, considerable attention has been given to OLs because of their remarkable content of polyphenols [15]. The most representative compounds of OLs are those illustrated in Figure 1. Table 1 shows most representative compounds present in olive leaves. To date, the best-known phenolic compounds in OLs are secoiridoid derivatives, of which OLE is the most abundant. Additionally, the presence of phenolic alcohols (e.g., HT, tyrosol, and oleoside) and flavones (e.g., LU and luteolin-7-o-glucoside) should be highlighted together with others.
Figure 1. Most representative phytochemical compounds in OL.
In the same way, other phenolic compounds, such as phenolic acids (e.g., verbascoside), flavanols (e.g., Epicatechin gallate), and flavonols (e.g., kaempferol-7-O-glucoside and rutin), have also been described in OLs (Figure 1). The phytochemical profile of the OL can be affected by several factors, such as the olive tree’s geographical location, cultivars, harvest season, drying temperature of leaves, and the solvents used for extraction. In this regard, Kabbash et al. (2021) demonstrated that olive leaves from Spain presented higher total flavonoid, phenolic, and OLE content compared with olive leaves from Italy and Egypt [16]. Similar results were obtained by Zhang et al. (2022), which showed a higher total flavonoid, OLE, and HT content, among other phenolic compounds, in Spanish olive leaves compared with those harvested in China or Italy [17]. These differences could also be attributed to the use of different cultivars. In this context, Nicoli et al. (2019) found significant differences among 15 different olive tree cultivars from Italy regarding OLE, HT, verbascoside (VB), and flavones (LU and luteolin-7-O-glucoside) content [18]. In the same way, Pasković et al. (2022) reported several differences in OLE, VB, rutin, catechin, phenolic alcohol (HT and tyrosol), and flavone (LU and apigenin derivatives) content in four different olive tree cultivars from Croatia [19]. Furthermore, the harvesting season has been demonstrated to influence the content of most of the phenolic compounds of OLs, even those of the same cultivar, with increases in olives harvested between March and April [16,19]. Additionally, it has been reported that the temperature of leaf drying after pruning can also affect the phenolic content. In this context, olive leaves dried using a freezing protocol (−80 °C) presented higher amounts of phytochemicals compared with those dried using a hot air protocol (105 °C), with the exception of OLE, the content of which increased in hot-air-dried olive leaves [17]. Authors attributed these results to the fact that some molecules, such as flavonoids, easily break down into smaller compounds during dehydration, while the stability of secoiroids, such as OLE, is relatively high. Finally, the method and solvent used for the extraction of olive leaf polyphenols has been reported to dramatically influence the final phenolic content. Most of the evaluated studies in this work used different proportions of methanol [19,20,21,22,23], ethanol [16,17,18], or water [23,24] as solvent to obtain the olive leaf extract. However, only Kontogianni et al. (2013) evaluated the direct influence of the solvent used in OL polyphenol extraction. Independently of the detection method (high performance liquid chromatography or nuclear magnetic resonance spectroscopy), the olive leaves extracted with methanol presented a higher content of OLE, HT, and LU and its derivatives compared with the aqueous OL extract. In fact, LU was not detected in the aqueous extract [23]. For further studies, the phytochemical characterization of OL needs to be standardized to generate a homogeneous phenolic profile through the regulation of the previously mentioned factors.
Table 1. Phytochemical characterization of olive leaves.
Table 1. Phytochemical characterization of olive leaves.
Phenolic CompoundCAS NumberMolecular FormulaRange of ContentRefs.
Phenolic acids
Verbascoside61276-17-3C29H36O159–465.63[18,19,20,22,24,25,26]
Gallic acid149-91-7C7H6O50.17–140[22,24,25]
Vanillin121-33-5C8H8O3nd–0.05[24,25]
Vanillic acid121-34-6C8H8O43–274[20,22,24]
p-coumaric acid501-98-4C9H8O3nd–4.41[20,24,25]
Ferulic acid537-98-4C10H10O4nd–0.96[24,25]
Chlorogenic acid327-97-9C16H18O9nd–26[17,20,22,24,25]
Neochlorogenic acid906-33-2C16H18O925[22]
Caffeic acid331-39-5C9H8O4nd–20.15[20,24,25]
Plantamajoside104777-68-6C29H36O16nd–1.35[17]
Rosmarinic acid20283-92-5C18H16O80.59[24]
Phenolic alcohols
Hydroxytyrosol10597-60-1C8H10O36.68–1092.74[17,19,23,25]
Hydroxytyrosol 4-O-glucoside54695-80-6C14H20O8nd–11.02[17]
p-Hydroxybenzoic acid99-96-7C7H6O33.63–141[20,22,24]
2,3-Dihydroxybenzoic acid303-38-8C7H6O42[22]
2,5-Dihydroxybenzoic acid490-79-9C7H6O41.18[24]
3,4-Dihydroxyphenylacetic acid102-32-9C8H8O40.62[24]
Protocatechuic acid99-50-3C7H6O417.61–965[20,24]
Tyrosol501-94-0C8H10O23.33–168.12[19,22,25]
Oleoside178600-68-5C16H22O1146[26]
Oleoside 11-methyl ester60539-23-3C17H24O1123[26]
Secoiridoid derivatives
Oleuropein32619-42-4C25H32O132.81–5940[16,17,18,19,20,21,22,23,25,26]
Secoxyloganin58822-47-2C17H24O111.80–138.32[17]
Ligstroside35897-92-8C25H32O1217[26]
Flavanols
Catechin18829-70-4C15H14O6nd–77[19,22,24]
Gallocatechin970-73-0C15H14O772[22]
Epicatechin490-46-0C15H14O6nd–2.17[22,24,25]
Epicatechin gallate1257-08-5C22H18O10133[22]
Epigallocatechin970-74-1C15H14O73[20]
Flavones
Luteolin491-70-3C15H10O6nd–266[17,18,19,20,22,23,24]
Luteolin-7-o-glucoside5373-11-5C21H20O1130–3978[17,18,19,20,22,23,24,25]
Luteolin-4′-O-glucoside6920-38-3C21H20O113.97–330[17,23]
Luteolin-3′,7-di-O-glucoside52187-80-1C27H30O166.37–31.38[17]
Diosmetin-7-O-neohesperidoside38665-01-9C28H32O150.21–1.27[17]
Apigenin520-36-5C15H10O5nd–9.38[17,19,22,24]
Apigenin-7-o-glucoside578-74-5C21H20O107.88–214.71[17,19,20,22,24,25]
Apigenin-7-O-neohesperidoside17306-46-6C27H30O1418.27–50.40[17]
Hispidulin1447-88-7C16H12O0.02–0.44[17]
Flavonols
Quercetin117-39-5C15H10O7nd–22[17,20,24]
Quercetin-3-o-glucoside482-35-9C21H20O126.48–31.65[17]
Quercetin-3-o-galactoside482-36-0C21H20O121.08–3.06[24,25]
Quercetin-4′-O-glucoside20229-56-5C21H20O12nd–1.83[17]
Rutin153-18-4C27H30O161.49–101[17,19,20,22,25,26]
Kaempferol520-18-3C15H10O6nd–1.18[17,20,24,25]
Kaempferol-7-O-glucoside16290-07-6C21H20O1162.19–268.11[17]
Tiliroside20316-62-5C30H26O130.48–1.85[17]
Flavanonols
Taxifolin480-18-2C15H12O70.32–27.43[17,24]
Taxifolin-3-glucoside27297-45-6C21H22O120.44–2.89[17]
Flavanones
Eriodictyol552-58-9C15H12O6nd–44.77[17,22,24]
Hesperidin520-26-3C28H34O15nd–5.72[22,24]
Coumarins
Esculin531-75-9C15H16O90.07–2.09[17]
Coumarin91-64-5C9H6O20.40–1.99[17]
Triterpenes
Asiatic acid464-92-6C30H48O50.88–2.88[17]
Oleanonic acid17990-42-0C30H46O368.15–226.70[17]
Maslinic acid4373-41-5C30H48O4323.55–607.14[17]
Corosolic acid4547-24-4C30H48O491.80–227.40[17]
Oleanolic acid508-02-1C30H48O3758.40–1047.67[17]
Ursolic acid77-52-1C30H48O314.64–25.89[17]
Other compounds
Quinic acid77-95-2C7H12O6605–2519[18]
Pyrocatechol120-80-9C6H6O21.03[24]
Pinoresinol487-36-5C20H22O6nd–1.56[24,25]
Range of content is expressed as milligrams per 100 g of dry weight. nd: no detectable.

3. Bioaccessibility and Bioavailability of Olive Leaf Polyphenols

A crucial point of drug administration is the capacity of the active principle to be absorbed and passed to the systemic circulation, and to exert its action on the specific sites. In the case of a multicomplex food matrix such as the OL, it is necessary to evaluate the absorption and metabolism of numerous compounds present in it, and to evaluate the role of these compounds in the observed healthy effects. Some studies have investigated the pharmacokinetics of olive leaf phenolics by administering isolated compounds (not explored in this review). However, in this review, the bioaccessibility and bioavailability of individual compounds were examined, but after OL administration.
According with in vitro studies, gastric, intestinal, and colonic digestion significantly reduced the bioaccessibility of numerous compounds naturally present in OLs, such as phenolic acids (e.g., VB, chlorogenic, gallic, and caffeic acid), phenolic alcohols (e.g., HT and tyrosol), secoiridoid derivatives (e.g., OLE), flavones (e.g., luteolin 7-o-glucoside, apigenin 7-o-glucoside), flavanols (e.g., epicatechin), and flavonols (i.e., quercetin-3-o-rutinoside, quercetin-3-o-galactoside, kaempferol, and rutin) [25,26]. However, in vitro digestion also promoted the bioaccessibility and the potential bioavailability of some secoiridoid derivatives related to OLE hydrolysis, such as oleoside and oleoside 11-methyl ester [26].
To date, only three investigations have explored the bioavailability of phenolic compounds from OLs in humans. As can be observed in Table 2, numerous compounds such as secoiridoid derivatives, phenolic alcohols, and flavonoids can be found in plasma or urine samples after OL ingestion. No significant influence of gender on the absorption of OL phenolic compounds was observed in middle-aged people after OL consumption (270 or 400 mg/d). Interestingly, the administration of OLs through liquid glycerol preparation increased the plasma bioavailability of OLE and reduced the time to peak of HT derivatives compared with softgel capsule administration [27].
Table 2. OL related metabolites found in plasma and urine samples in humans.
According to the pharmacokinetics, the biological half-life of plasma OLE metabolites (1.33–2.01 h) was shorter than that of HT derivatives (1.73–6.53 h), whereas the excretion peak rate in urine was 8-24 h for both metabolite classes [28,29]. The most abundant compounds found in urine were secoiridoids and HT and its derivatives, probably due to the rapid hydrolysis of OLE in the upper gastrointestinal tract [28,29]. It should be noted that the hydrolysis of OLE is not complete and numerous glucuronidated and sulfated derivatives from OLE can be found in plasma and urine, indicating that OLE is also conjugated by Phase II enzymes [29]. Curiously, a study of pre- and post-menopausal women fed with 250 mg of OL revealed that OL-related metabolites, such as HT glucuronide and sulfate, OLE aglycone glucuronide, and aglycon derivative I, were present in higher concentrations in the plasma from post-menopausal women. The authors attributed these results to potential age-related changes such as alterations in hormonal status and a decrease in gastric emptying [29]. These results are extremely interesting due the existence of a potential increase of bioavailability of phenolic compounds from OL, related, at least in part, to women’s age, opening the door to their potential use in aging and age-related diseases.

4. Toxicological Evaluation of Olive Leaves Bioactive Compounds

Olive leaves have been widely used as therapeutic tools throughout history [30]. In contrast to the classical belief that botanic-related products are completely safe and lack toxicity, these products could cause several side effects due to the fact that most of their chemical content remains uncharacterized. In addition, due to the easy access and low cost of these by-products, as well as the possibility of self-medication without medical advice for many people around the world, the study of OL-related toxicity is necessary. Therefore, in this section, the evidence regarding toxicity related to the intake of olive leaves is discussed.
According to in vitro studies, the co-incubation of different concentrations (51.2, 128, 320, 800, 2000, and 5000 µg/mL) of OL did not reveal pro-mutagenic effect in different Salmonella typhimurium (TA98, TA100, TA1535, and TA1537) and Escherichia coli (WP2 uvrA) strains in the Bacterial Reverse Mutation Test [31]. In the same way, coincubation with rising concentrations of OL (250, 500, 750, 1000, and 1250 µg/mL) did not affect the number of aberrant cells, polyploidy rates, or endoreduplication metaphases in V79 male Chinese hamster lung cells in the Chromosomal Aberration Test [31]. Similarly, treatment with lower OL dosages (20, 40, 60, 70, or 80 µg/mL) was demonstrated not to reduce or even increase viability in different cell lines [32,33].
Acute toxicity of OLs has also been evaluated in in vivo models. In this context, no adverse reactions, toxicity clinical signs, or lethality were observed after 24–48 h of OL administration in Caenorhabditis elegans (0.1, 1, 10, 100, 1000 µg/mL, [C. elegans]), NMRI BR mice (500, 1000, and 2000 mg/kg of body weight [bw]), or Swiss albino mice (2000 mg/kg bw) [31,34,35]. In fact, no genotoxic activity of OL was observed in bone marrow from these NMRI BR mice consuming 500, 1000, or 2000 mg/mL for 48 h [31] or Drosophila melanogaster acutely exposed to 3.75 or 30 µg/mL of OL [36]. Additionally, no embryolethality or embryotoxicity were found after an acute exposure to 100 µg/mL of OL for 24 h in C. elegans Wild-type strain [35]. Regarding sub-chronic toxicity of OL, the intake of 100, 200, 400, or 2000 mg/kg bw of OL daily via gavage for 14 or 28 days did not produce mortality, signs of toxicity, or behavioral and physical alterations in Wistar male and female rats. In addition, necropsy showed no abnormalities in the liver and kidney of treated rats [37]. Similar results were obtained in Wistar rats orally supplemented with 360, 600, or 1000 mg/kg bw of OL daily for three months [31]. Additionally, these authors found no alterations in organ weight (liver, adrenals, kidneys, thyroid/parathyroid, thymus, spleen, brain, heart, epididymides, testes, ovaries, fallopian tubes, and uterus) or pathological lesions in the most representative organs from locomotor, digestive, lymphatic, integumentary, respiratory, cardiovascular, endocrine, excretory, reproductive, and central and peripheral nervous systems [31]. Similarly, the consumption of 250 mg/day of OL in a double-blind, randomized controlled trial for 12 months revealed an absence of side effects in aged women [38]. In accordance with chronic toxicity, only one study evaluated the long-life effect of OL. In this context, lifelong administration of 100 µg/mL did not modify the survival rates in the C. elegans Wild-type strain [35].
Among the in vivo endpoint studies, some research has evaluated the influence of OL treatment in biochemical and hematological parameters. Interestingly, after an acute administration of 2000 mg/kg bw of OL, some hematological (hematocrit, hemoglobin, mean corpuscular volume, red blood cells, and platelets) and biochemical parameters (cholesterol and creatinine levels) were reduced without producing abnormalities in liver or kidneys [37]. It should be noted that the solvent used in this work was a solution made with 51% of ethanol, which could also interfere in hematological and biochemical studies, meaning results may not be attributed to the treatment itself. In fact, when the same solvent was administered for 28 days, the effect on hematological and biochemical parameters disappeared, probably due to an adaptation to alcohol consumption [37]. Similarly, the intake of 360, 600, or 1000 mg/kg bw of OL diluted in distilled water daily for three months did not alter most of the hematological parameters, electrolytes, or renal and hepatic markers studied in rats [31]. According to hepatic markers, no adverse effects were noted related to aspartate and alanine aminotransferase, gamma glutamyl transferase, and alkaline phosphatase levels in middle-aged people who consumed 270 or 400 mg of OL [27]. Similarly, no clinical changes were observed in classical biochemistry, hematological, or electrolytes parameters, or renal- and liver-function-related parameters, in a randomized controlled trial that administered 1000 mg/day of OL for 8 weeks [39].

Funding

This work has been partially supported by the grants PID2019-106778RB-I00, funded by MCIN/AEI/10.13039/501100011033 FEDER “Una manera de hacer Europa”, and SUSTAINOLIVE (PRIMA H2020-1811).

Acknowledgments

María D. Navarro-Hortal and José M. Romero-Márquez are FPU fellows with grant reference FPU2017/04358 and FPU2018/05301, respectively, funded by MCIN/AEI/10.13039/501100011033 and FSE “El FSE invierte en tu futuro”. Tamara Forbes-Hernández is supported by a JdC-I post-doctoral contract with grant reference IJC2020-043910-I, funded by NextGenerationEU. Authors are indebted with Monica Glebocki for extensive editing of the manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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