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

J Alzheimers Dis. 2018;63(3):1161-1172. doi: 10.3233/JAD-171124.


Alzheimer's disease is the most common form of dementia affecting a large proportion of aged people. Plant polyphenols have been reported to be potentially useful in the prevention of AD due to their multiple pharmacological activities. The aim of the present study was to assess whether the previously reported neuroprotective and anti-inflammatory effects resulting from oleuropein aglycone administration were reproduced by diet supplementation with similar amounts of its metabolite hydoxytyrosol (HT). Four-month-old TgCRND8 and wild type mice were treated for 8 weeks with a low-fat diet (5%) supplemented with HT (50 mg/kg of diet). We found that HT supplementation significantly improved cognitive functions of TgCRND8 mice and significantly reduced Aβ42 and pE3-Aβ plaque area and number in the cortex; in the hippocampal areas of HT-fed TgCRND8 mice, we found a significant reduction in the pE3-Aβ plaque number together with a tendency toward a reduction in Aβ42 load and pE3-Aβ plaque area, associated with a marked reduction of TNF-α expression and astrocyte reaction. Macroautophagy induction and modulation of MAPKs signaling were found to underlie the beneficial effects of HT. Our findings indicate that HT administration reproduces substantially the beneficial effects on behavioral performance and neuropathology previously reported in TgCRND8 mice fed with oleuropein aglycone, resulting in comparable neuroprotection.

Keywords: Amyloid plaques; MAPKs signaling; autophagy; hydoxytyrosol; memory function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Amyloidosis, Familial / metabolism
  • Animals
  • Antioxidants / therapeutic use*
  • Autophagy / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Cognition Disorders / diet therapy*
  • Cognition Disorders / etiology*
  • Corneal Dystrophies, Hereditary / metabolism
  • Diet*
  • Disease Models, Animal
  • Glial Fibrillary Acidic Protein / metabolism
  • Maze Learning / drug effects
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mutation / genetics
  • Phenylethyl Alcohol / analogs & derivatives*
  • Phenylethyl Alcohol / therapeutic use
  • Presenilin-1 / genetics
  • RNA, Messenger / metabolism
  • Signal Transduction / drug effects
  • Tumor Necrosis Factor-alpha / metabolism


  • Amyloid beta-Protein Precursor
  • Antioxidants
  • Glial Fibrillary Acidic Protein
  • PSEN1 protein, human
  • Presenilin-1
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • 3,4-dihydroxyphenylethanol
  • Phenylethyl Alcohol

Supplementary concepts

  • Corneal dystrophy, gelatinous drop-like