Neuroprotective Function of Hydroxytyrosol and Oleuropein in Alzheimer’s Disease

Alzheimer's Disease is a neurodegenerative disease associated with cognitive impairment in mid- and late-life. It is characterized by the formation of senile plaques (containing β-amyloid or Aβ peptide) and neurofibrillary tangles (NFT, composed of hyperphosphorylated Tau protein). Tau normally binds to microtubules, but in its hyperphosphorylated form, it cannot bind properly, leading to microtubule instability, disrupted cellular traffic, synapse loss, cognitive decline, and dementia.


Several processes contribute to the hyperphosphorylation of Tau, including Aβ peptides, impaired glucose metabolism, and inflammation. Aβ peptides are a major component of senile plaques and play a key role in Alzheimer's disease pathogenesis. They result from the amyloidogenic metabolism of amyloid precursor protein (APP) and tend to aggregate into plaques.


Hydroxytyrosol and oleuropein have been found to inhibit the fibrillization of Tau protein, reducing intraneuronal and glial lesions. They also prevent the aggregation of Aβ peptides, including Aβ1–42 oligomers, in neuroblastoma cells and mouse models of Alzheimer's disease. This prevention is associated with improvements in spatial and associative memory. These compounds have additional beneficial effects, such as preventing insulin secretion issues, amylin deposition, and α-synuclein aggregation. They also promote autophagy, a cellular process for removing dysfunctional components, which is relevant to Alzheimer's disease.


Hydroxytyrosol has been shown to induce mitochondrial generation and fusion, which can counteract mitochondrial dysfunction seen in Alzheimer's disease. It helps in reducing the accumulation of reactive oxygen species (ROS) and the impairment of mitochondrial function.


Hydroxytyrosol and tyrosol have been found to protect against cell death and inflammation caused by Aβ oligomers in neuroblastoma cells. They also restore insulin signaling in astrocytes, which is important for neuronal functioning.


In summary, hydroxytyrosol and oleuropein appear to have several potential beneficial effects on the pathology and symptoms of Alzheimer's disease, including inhibiting Tau and Aβ aggregation, promoting autophagy, improving mitochondrial function, and providing neuroprotection. However, the dosage and timing of treatment may be critical factors in achieving these effects. Further research is needed to fully understand their therapeutic potential for Alzheimer's disease.



1.    A century of Alzheimer's disease 

2.    The role of tau in Alzheimer's disease and related disorders 

3.    The role of cerebral amyloid beta accumulation in common forms of Alzheimer disease 

4.    Oleuropein and derivatives from olives as Tau aggregation inhibitors

5.    Aβ(1-42) Aggregates into Non-Toxic Amyloid Assemblies in the Presence of the Natural Polyphenol Oleuropein Aglycon

6.    3,4-Dihydroxyphenylethanol Attenuates Spatio-Cognitive Deficits in an Alzheimer’s Disease Mouse Model: Modulation of the Molecular Signals in Neuronal Survival-Apoptotic Programs

7.    Diet Supplementation with Hydroxytyrosol Ameliorates Brain Pathology and Restores Cognitive Functions in a Mouse Model of Amyloid-β Deposition

8.    Oleuropein aglycone protects against pyroglutamylated-3 amyloid-ß toxicity: Biochemical, epigenetic and functional correlates

9.    Oleuropein aglycone and polyphenols from olive mill waste water ameliorate cognitive deficits and neuropathology

10.  Oleuropein Aglycone Protects Transgenic C. elegans Strains Expressing Aβ42 by Reducing Plaque Load and Motor Deficit

11.  Olive Component Oleuropein Promotes β-Cell Insulin Secretion and Protects β-Cells from Amylin Amyloid-Induced Cytotoxicity. 

12.  Oleuropein aglycone stabilizes the monomeric α-synuclein and favours the growth of non-toxic aggregates 

13.  Melatonin, protocatechuic acid and hydroxytyrosol effects on vitagenes system against alpha-synuclein toxicity

14.  Hydroxytyrosol mildly improve cognitive function independent of APP processing in APP/PS1 mice

15.  Hydroxytyrosol Acetate Improves the Cognitive Function of APP/PS1 Transgenic Mice in ERβ-dependent Manner

16.  Hydroxytyrosol improves mitochondrial energetics of a cellular model of Alzheimer’s disease

17.  EVOO Polyphenols Relieve Synergistically Autophagy Dysregulation in a Cellular Model of Alzheimer’s Disease

18.  Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-β-induced toxicity. Involvement of the NF-κB signaling

19.  Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer’s disease

20.  Oleuropein aglycone and hydroxytyrosol interfere differently with toxic Aβ1-42 aggregation

21.  Natural Compounds and Autophagy: Allies Against Neurodegeneration