The protection of hydroxytyrosol against neurodegenerative diseases

Hydroxytyrosol (HT), a representative olive polyphenol, exhibits multi-target and multi-pathway intervention mechanisms in Alzheimer's disease (AD) and Parkinson's disease (PD) models. Research has extended from molecular mechanisms and cellular models to animal experiments, providing potential strategies for disease prevention and treatment. The following is a systematic analysis based on model studies:

I. Neuroprotective Foundations of Hydroxytyrosol: Core Mechanisms of Antioxidation and Anti-inflammation

The molecular structure of hydroxytyrosol (3,4-dihydroxyphenethyl alcohol) endows it with strong antioxidant capacity. Its phenolic hydroxyl groups scavenge reactive oxygen species (ROS) such as hydroxyl radicals (・OH) and superoxide anions (O₂・⁻), and chelate metal ions (e.g., Fe²⁺, Cu²⁺) to inhibit free radical generation. In AD and PD models, HT reduces lipid peroxidation products (e.g., malondialdehyde, MDA) and protein carbonylation by upregulating endogenous antioxidant enzymes (e.g., superoxide dismutase, SOD; glutathione peroxidase, GPx), alleviating oxidative stress-induced neuronal damage.

Additionally, hydroxytyrosol suppresses excessive microglial activation, reducing the release of pro-inflammatory factors (e.g., TNF-α, IL-1β) and nitric oxide (NO) to block neuroinflammatory cascades. In lipopolysaccharide (LPS)-induced PD cell models, HT inhibits the NF-κB signaling pathway, reduces inducible nitric oxide synthase (iNOS) expression, and thereby decreases neuronal apoptosis.

II. Intervention in Alzheimer's Disease Models: Targeting Aβ Deposition and Tau Protein Abnormalities

1. Bidirectional Regulation of Aβ Aggregation and Clearance

In APP/PS1 transgenic AD mice, hydroxytyrosol (50–100 mg/kg/d gavage) influences Aβ metabolism through:

Inhibiting Aβ production: Downregulating β-secretase (BACE1) and γ-secretase activities to reduce Aβ40/42 generation;

Promoting Aβ clearance: Upregulating low-density lipoprotein receptor-related protein 1 (LRP1) expression to enhance BBB-mediated Aβ transport and activating macrophage phagocytosis.

In vitro, HT directly binds to Aβ oligomers (AβO), disrupts their β-sheet structure, inhibits fibril formation, and reduces AβO toxicity in SH-SY5Y neuroblastoma cells (e.g., mitigating mitochondrial membrane potential decline and Caspase-3 activation).

2. Regulation of Tau Protein Phosphorylation

In PC12 cells overexpressing tau protein, hydroxytyrosol (10–20 μM) reduces excessive phosphorylation of tau at Ser396/Ser404 by inhibiting glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (CDK5), thereby suppressing neurofibrillary tangles (NFTs). Animal studies show HT decreases brain phosphorylated tau (p-tau) levels in AD model mice and improves hippocampal neuronal synaptic plasticity (e.g., increasing postsynaptic density protein PSD-95 expression).

III. Protective Effects in Parkinson's Disease Models: Focus on Dopaminergic Neurons and α-Synuclein

1. Maintenance of Dopaminergic Neuron Survival

In PD animal models induced by 6-hydroxydopamine (6-OHDA) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), HT (intraperitoneal injection or gavage) significantly reduces dopaminergic neuron loss in the substantia nigra pars compacta and increases striatal dopamine levels by:

Mitochondrial protection: Activating the AMPK/mTOR pathway to promote mitophagy, clear damaged mitochondria, maintain mitochondrial membrane potential and respiratory chain complex activity, and reduce cytochrome C-mediated apoptosis;

Anti-apoptotic signaling: Upregulating the Bcl-2/Bax ratio and inhibiting Caspase-9/-3 activation. In rotenone-induced SH-SY5Y cells, HT increases cell viability by >40%.

2. Inhibition of α-Synuclein (α-syn) Aggregation

In α-syn overexpressing PD models (e.g., transgenic flies or mice), hydroxytyrosol intervenes via:

Direct binding to α-syn: Disrupting α-syn β-sheet structures through hydrophobic interactions and hydrogen bonds to reduce fibril formation and neuronal toxicity;

Regulating the autophagy-lysosome pathway: Activating transcription factor EB (TFEB) to promote autophagosome-lysosome fusion, accelerating α-syn degradation and reducing Lewy body deposition.

IV. Blood-Brain Barrier Permeability and Pharmacokinetic Advantages

Hydroxytyrosol's lipophilicity (log P≈1.5) facilitates its passage through the blood-brain barrier (BBB). In rodent experiments, brain concentrations peak at 1–2 hours post-gavage (≈1–5 μM) with a long half-life (≈4–6 hours). Metabolites (e.g., hydroxytyrosol glucuronide) retain partial antioxidant activity, synergizing neuroprotection. Moreover, HT is not easily metabolized by catechol-O-methyltransferase (COMT), avoiding rapid inactivation similar to dopamine—a feature enhancing its potential in PD models.

V. Challenges and Prospects for Clinical Translation

While hydroxytyrosol shows significant neuroprotection in preclinical studies, clinical translation faces:

Dose and safety: Effective animal doses (50–200 mg/kg/d) require toxicity evaluation (e.g., hepatic/renal effects) in human trials to determine the maximum tolerated dose via Phase I;

Formulation optimization: HT's oxidative polymerization necessitates nano-delivery systems (e.g., liposomes, PLGA microspheres) for stability and brain targeting;

Combination therapy: In AD models, HT combined with cholinesterase inhibitors (e.g., donepezil) enhances cognitive improvement, indicating combination strategies as a future direction.

Notably, HT's natural sources (olive oil, olive leaf extract) enable dietary intervention. Observational studies show an inverse correlation between HT intake in the Mediterranean diet and AD/PD risk, providing epidemiological support for preventive use.

VI. Conclusion

Hydroxytyrosol exhibits neuroprotective effects in AD and PD models through multi-pathways—antioxidation, anti-inflammation, protein aggregation regulation, and mitochondrial protection—addressing core pathological links of disease onset. Future research should optimize dosing based on preclinical findings and explore synergies with other drugs to advance translation from bench to bedside.