Entry #: 18
Date: 21 October 2017
Section: Neurodegeneration
Topic: Hydroxytyrosol and Alzheimer’s disease
Type: In vitro study

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Expert review of literature related to olives and olive oil

D. Elizabeth McCord, Nancy B. Ray and Tom C. Karagiannis


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


Crespo et al

Citation / Year

(1) / 2017


Hydroxytyrosol, Alzheimer’s disease, neurodegeneration, astrocytes, insulin signaling, amyloid beta


This study has been motivated by the 1) accumulating evidence indicating that the Mediterranean diet characterized in part by the consumption of extra-virgin olive oil, is associated with improved cognition and benefits in neurodegenerative conditions, particularly Alzheimer’s disease (2, 3) and 2) meta-analyses suggesting that diabetes (including type 2 diabetes in 90% of cases) increases the risk for Alzheimer’s disease by 50-100% (4, 5). Insulin resistance has been suggested as the main link between diabetes and Alzheimer’s disease and indeed, the term “type III diabetes” has been coined by some researchers to describe Alzheimer’s disease (6, 7). Given these links the authors performed a series of in vitro experiments to investigate the effects of hydroxytyrosol (a major olive polyphenol) on insulin signaling in an astrocytic cell culture model of Alzheimer’s disease. The authors chose astrocytes (cerebral microglial cells) given their proximity to senile amyloid plaques in Alzheimer’s disease and their central metabolic role on which neurons are dependent. Importantly, it was previously shown that the pathogenic amyloid beta Ab(1-42) peptide has detrimental effects on insulin signaling and glycogen storage in human astrocytes (8, 9). In the current experiments the authors established a cell culture model using an Aβ(25-35) peptide which displays cytotoxicity and self-aggregating properties (10). Conventional cellular and molecular studies were conducted to investigate the effects of pre-(prevention) and post-treatment (reversal) with 25 μM hydroxytyrosol on Aβ(25-35)-induced reductions in cell viability and modulation of insulin signaling in C6 rat glioma astrocytes.

Key points and implications

The results from the cell viability assays were particularly impressive indicating that while 25 μM hydroxytyrosol was not toxic to the cells, the Aβ(25-35) peptide reduced cell viability by ~50%. This reduction in cell viability by the Aβ(25-35) peptide was attenuated by hydroxytyrosol with 24 hour control showing much more pronounced effects (viability restored to ~100%), than pre-treatment with hydroxytyrosol for two hour prior to the addition of the Aβ(25-35) peptide (viability increased to ~70% compared to ~50% with peptide alone). In summary, immunoblotting experiments highlighted the beneficial effects of hydroxytyrosol on insulin signaling in Aβ(25-35) peptide-treated astrocytes with restored: 1) hyperphosphorylation of insulin receptor substrate 1, 2) association between p85 and IRS1, 3) Akt activation, 4) GLUT2 expression, and 5) expression of phosphorylated mTOR levels. Overall, these findings provide important molecular mechanistic insights into the biological effects of hydroxytyrosol on insulin signaling in a cell culture model of Alzheimer’s disease. More generally, the findings can be considered as a critical starting point for ultimately understanding the detailed molecular basis for the beneficial effects of the Mediterranean diet and neurodegenerative conditions.

Related publications

  1. M. C. Crespo et al., Hydroxytyrosol restores proper insulin signaling in an astrocytic model of Alzheimer’s disease. BioFactors 43, 540-548 (2017).
  2. O. van de Rest, A. A. Berendsen, A. Haveman-Nies, L. C. de Groot, Dietary patterns, cognitive decline, and dementia: a systematic review. Advances in nutrition 6, 154-168 (2015).
  3. E. H. Martinez-Lapiscina et al., Virgin olive oil supplementation and long-term cognition: the PREDIMED-NAVARRA randomized, trial. The journal of nutrition, health & aging 17, 544-552 (2013).
  4. M. N. Haan, Therapy Insight: type 2 diabetes mellitus and the risk of late-onset Alzheimer’s disease. Nature clinical practice. Neurology 2, 159-166 (2006).
  5. L. A. Profenno, A. P. Porsteinsson, S. V. Faraone, Meta-analysis of Alzheimer’s disease risk with obesity, diabetes, and related disorders. Biological psychiatry 67, 505-512 (2010).
  6. G. Accardi et al., Can Alzheimer disease be a form of type 3 diabetes? Rejuvenation research 15, 217-221 (2012).
  7. R. Kandimalla, V. Thirumala, P. H. Reddy, Is Alzheimer’s disease a Type 3 Diabetes? A critical appraisal. Biochimica et biophysica acta 1863, 1078-1089 (2017).
  8. Q. Zhang et al., Amyloid beta oligomer-induced ERK1/2-dependent serine 636/639 phosphorylation of insulin receptor substrate-1 impairs insulin signaling and glycogen storage in human astrocytes. Gene 561, 76-81 (2015).
  9. X. Han et al., Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes. Cellular and molecular neurobiology 36, 851-864 (2016).
  10. K. Yamada, T. Nabeshima, Animal models of Alzheimer’s disease and evaluation of anti-dementia drugs. Pharmacology & therapeutics 88, 93-113 (2000).