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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurosci. | doi: 10.3389/fnins.2019.00249

The Crocus sativus compounds trans-crocin 4 and trans-crocetin modulate the amyloidogenic pathway and tau misprocessing in Alzheimer disease neuronal cell culture models

  • 1Clinical Genomics and Pharmacogenomics Unit, 4th Department of Internal Medicine, “Attikon” Hospital, National and Kapodistrian University of Athens Medical School, Greece
  • 2Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Greece
  • 3GAIA Research Center, Bioanalytical Department, The Goulandris Natural History Museum, Greece
  • 4Department of Pharmacognosy and Natural Product Chemistry, Faculty of Pharmacy,, National and Kapodistrian University of Athens, Greece

Crocus sativus L. natural compounds have been extensively used in traditional medicine for thousands of years. Recent research evidence is now emerging in support of its therapeutic potential for different pathologies including neurodegenerative diseases. Herein, the Crocus sativus L. natural compounds trans-crocin 4 and trans-crocetin were selected for in depth molecular characterization of their potentially protective effects against Alzheimer’s Disease (AD), utilizing two AD neuronal cell culture models (SH-SY5Y overexpressing APP and PC12 expressing hyperphosphorylated tau). Biologically relevant concentrations, ranging from 0.1 μM to 1 mM, applied for 24h or 72h, were well tolerated by differentiated wild type SH-SY5Y and PC12 cells. When tested on neuronally differentiated SH-SY5Y-APP both trans-crocin 4 and trans-crocetin had significant effects against amyloidogenic pathways. Trans-crocin 4 significantly decreased of β-secretase, a key enzyme of the amyloidogenic pathway, and APP-C99, while it decreased γ-secretases that generate toxic beta-amyloid peptides. Similarly, trans-crocetin treatment led to a reduction in β- and γ-secretases, as well as to accumulation of cellular ΑβPP. When tested on the neuronally differentiated PC12-htau cells, both compounds proved effective in suppressing the active forms of GSK3β and ERK1/2 kinases, as well as significantly reducing total tau and tau phosphorylation. Collectively, our data demonstrate a potent effect of trans-crocin 4 and trans-crocetin in suppressing key molecular pathways of AD pathogenesis, rendering them a promising tool in the prevention and potentially the treatment of AD.

Keywords: Neurodegenerative Diseases, Crocus sativus, Trans-crocetin, trans-crocin 4, Alzheimer ' s disease, Tau phosphorylation, beta-amyloid pathway, natural compounds

Received: 02 Aug 2018; Accepted: 04 Mar 2019.

Edited by:

Corinne Lasmezas, The Scripps Research Institute, United States

Reviewed by:

Federico Herrera, Instituto de Tecnologia Química e Biológica (ITQB-NOVA), Portugal
Stefan F. Weiss, University of the Witwatersrand, South Africa  

Copyright: © 2019 Chalatsa, Arvanitis, Koulakiotis, Giagini, Skaltsounis, TSARBOPOULOS and Sanoudou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Despina Sanoudou, National and Kapodistrian University of Athens Medical School, Clinical Genomics and Pharmacogenomics Unit, 4th Department of Internal Medicine, “Attikon” Hospital, Athens, Greece, dsanoudou@bioacademy.gr