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

International Journal of Molecular Sciences · 10 authors, 10 centres

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This narrative review examines how olive leaf polyphenols—particularly oleuropein and hydroxytyrosol—may protect against Alzheimer's disease through multiple molecular mechanisms. The compounds reduce amyloid-β aggregation and tau protein hyperphosphorylation, inhibit acetylcholinesterase, attenuate neuroinflammation via NF-κB pathway modulation, and decrease oxidative stress through Nrf2 activation and antioxidant enzyme upregulation. Although most evidence comes from in vitro and animal studies, the findings suggest olive leaf extracts could serve as an adjuvant nutritional strategy for Alzheimer's prevention, though clinical trials remain limited.

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**Background:** Alzheimer's Disease (AD) accounts for approximately 60–70% of global dementia cases, affecting around 50 million people worldwide, with incidence rates doubling every 5 years from age 60. The disease is characterized by two histopathological hallmarks: senile plaques formed by amyloid-β (Aβ) peptides and neurofibrillary tangles (NFTs) from hyperphosphorylated tau protein. These events are accompanied by mitochondrial dysfunction, oxidative stress, neuroinflammation, and proteostatic disturbances. Modifiable risk factors, including diet, account for an estimated 35% of dementia cases. The Mediterranean Diet, rich in phenolic compounds from olive products, has been associated with reduced AD incidence. Olive leaves (OL), a major by-product of olive grove industry generating 1–5 tons of waste per hectare in Spain, contain abundant bioactive polyphenols, with oleuropein (OLE) being the most abundant secoiridoid derivative, alongside hydroxytyrosol (HT), luteolin, verbascoside, and numerous other phenolic compounds.

**Methods:** This is a narrative review synthesizing evidence from in vitro studies, animal models, and human trials regarding the effects of olive leaf polyphenols on molecular mechanisms related to AD. The review covers phytochemical characterization, bioaccessibility/bioavailability, toxicological evaluation, and effects on Aβ aggregation, tau pathology, neurotransmitter-degrading enzymes, neuroinflammation, oxidative stress, and autophagy/proteostasis.

**Key Results:** In vitro studies demonstrated that OLE (IC50: 22.9 μM), HT (IC50: 30.4 μg/mL), verbascoside (IC50: 22.6 μM), luteolin (IC50: 36.9 μM), and quercetin (IC50: 45.9 μM) reduced Aβ42 fibril formation. Olive leaf extract (40% OLE) at 100 μg/mL reduced Aβ-induced toxicity and deposits in C. elegans models through DAF-16/FOXO, SKN-1/Nrf2, and HSP16.2 pathways. In 5xFAD mice, oral supplementation with OL (695 μg/kg/day for 3 months) reduced total Aβ deposits in hippocampus and cortex, decreased soluble Aβ40 levels, increased expression of Aβ clearance proteins (P-gp and LRP1), and modulated APP processing (increased sAPPα and α-secretase, decreased sAPPβ). In APPswe/PS1dE9 mice, OL (50 mg/kg/day for 16 weeks) reduced Aβ plaque number and size. Tau-related effects included improved locomotion parameters in C. elegans and reduced p-Tau in rabbit spinal cord injury models. For enzyme inhibition, olive leaf extracts showed BACE-1 inhibitory activity (IC50: 18 ng for olive fruit extract, 2.7 μM for OLE, 0.26 μM for HT), and AChE/BChE inhibition was observed with whole extracts but not isolated compounds, suggesting synergistic effects. Anti-inflammatory effects in 5xFAD mice included reduced astrocyte and microglial activation, decreased IL-1β and NLRP3 levels, and modulation of NF-κB pathway components (reduced p-IKKβ and p-IκBα, increased total IκBα). RAGE and HMGB1 protein levels were downregulated. In human PBMCs from male patients consuming 20 mL liquid OL extract (121.8 mg OLE and 6.4 mg HT daily for 8 weeks), downregulation of COX-2, IL-8, and jun-B gene expression was observed. Oxidative stress attenuation was demonstrated through reduced ROS content, increased antioxidant enzyme activities (SOD, CAT, GSH-Px, GST), and Nrf2 pathway activation. In aged Wistar rats, OL (50 mg/kg/day for 6 months) increased midbrain SOD, GPX, and CAT activities while reducing MDA levels. Autophagy modulation studies showed that an OLE aglycone/HT mix (75 μM) reduced p62 levels and S6 phosphorylation in SH-SY5Y cells exposed to Aβ1–42, indicating enhanced autophagic flux. Bioavailability studies in humans showed that OL metabolites (HT glucuronide/sulfate, OLE aglycone glucuronide) appear in plasma and urine, with higher concentrations in post-menopausal women. Toxicological evaluation found no adverse effects at doses up to 2000 mg/kg bw in rodents and 1000 mg/day in humans for 8 weeks.

**Clinical Implications:** Olive leaf polyphenols demonstrate multi-target effects against AD pathology, including anti-amyloid, anti-tau, anti-inflammatory, antioxidant, and autophagy-modulating properties. The favorable safety profile and bioavailability in humans support potential use as a nutritional adjuvant for AD prevention, particularly given that 35% of dementia cases are linked to modifiable lifestyle factors. However, most evidence comes from preclinical studies, and the limited human trials have focused on bioavailability and safety rather than cognitive outcomes. The review notes that behavioral testing in animal models has yielded inconsistent results, with some studies failing to detect improvements in locomotion or anxiety despite reduced pathology. Standardization of OL extracts and more clinical research are needed before therapeutic recommendations can be made.

STUDY TYPE

narrative_review

SPECIALTY

neurology

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ORIGINAL PAPER

PMC10001635

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

International Journal of Molecular Sciences

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ABSTRACT

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. Keywords: olive leaves, bioactive compounds, Alzheimer’s Disease, oleuropein, hydroxytyrosol

CITATION EXPORT

Jose M Romero-Márquez, Tamara Y Forbes-Hernández, María D Navarro-Hortal et al.. Molecular Mechanisms of the Protective Effects of Olive Leaf Polyphenols against Alzheimer’s Disease. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms24054353

AUTHORS

10 · 10 CENTRES

Jose M Romero-Márquez, Tamara Y Forbes-Hernández, María D Navarro-Hortal, Rosa Quirantes-Piné, Giuseppe Grosso, Francesca Giampieri, Vivian Lipari, Cristina Sánchez-González, Maurizio Battino, José L Quiles

1Department of Physiology, Institute of Nutrition and Food Technology “José Mataix Verdú”, Biomedical Research Centre, University of Granada, 18016 Armilla, Spain
2Research and Development Functional Food Centre (CIDAF), Health Science Technological Park, Avenida del Conocimiento 37, 18016 Granada, Spain
3Department of Biomedical and Biotechnological Sciences, University of Catania, 95123 Catania, Italy
4Center for Human Nutrition and Mediterranean Foods (NUTREA), University of Catania, 95123 Catania, Italy
5Research Group on Foods, Nutritional Biochemistry and Health, Universidad Europea del Atlántico, Isabel Torres 21, 39011 Santander, Spain
6Department of Project Management, Universidad Internacional Iberoamericana, Campeche 24560, Mexico
7Department of Prohect Management, Universidade Internacional do Cuanza, Cuito 250, Bié, Angola
8Sport and Health Research Centre, University of Granada, C/Menéndez Pelayo 32, 18016 Granada, Spain
9Department of Clinical Sciences, Polytechnic University of Marche, 60131 Ancona, Italy
10International Joint Research Laboratory of Intelligent Agriculture and Agri-Products Processing, Jiangsu University, Zhenjiang 212013, China