Vitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation

  • Int J Mol Sci. 2017 Dec 19;18(12):2764. doi: 10.3390/ijms18122764.
Marcus O W Grimm  1  2  3 ,  Andrea Thiel  4 ,  Anna A Lauer  5 ,  Jakob Winkler  6 ,  Johannes Lehmann  7  8 ,  Liesa Regner  9 ,  Christopher Nelke  10 ,  Daniel Janitschke  11 ,  Céline Benoist  12 ,  Olga Streidenberger  13 ,  Hannah Stötzel  14 ,  Kristina Endres  15 ,  Christian Herr  16 ,  Christoph Beisswenger  17 ,  Heike S Grimm  18 ,  Robert Bals  19 ,  Frank Lammert  20 ,  Tobias Hartmann  21  22  23
Affiliations
  • 1. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 2. Neurodegeneration and Neurobiology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 3. Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 4. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 5. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 6. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 7. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 8. Department of Internal Medicine II-Gastroenterology, Saarland University Hospital, Saarland University, Kirrberger Str. 100, 66421 Homburg/Saar, Germany. [email protected].
  • 9. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 10. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 11. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 12. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 13. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 14. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 15. Department of Psychiatry and Psychotherapy, Clinical Research Group, University Medical Centre Johannes Gutenberg, University of Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany. [email protected].
  • 16. Department of Internal Medicine V-Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 17. Department of Internal Medicine V-Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 18. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 19. Department of Internal Medicine V-Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 20. Department of Internal Medicine II-Gastroenterology, Saarland University Hospital, Saarland University, Kirrberger Str. 100, 66421 Homburg/Saar, Germany. [email protected].
  • 21. Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 22. Neurodegeneration and Neurobiology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
  • 23. Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany. [email protected].
PMID: 29257109 DOI: 10.3390/ijms18122764
Abstract

Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of Amyloid-β (Aβ), as derived from sequential cleavage of the amyloid precursor protein. Epidemiological studies suggest a tight link between hypovitaminosis of the secosteroid vitamin D and AD. Besides decreased vitamin D level in AD patients, an effect of vitamin D on Aβ-homeostasis is discussed. However, the exact underlying mechanisms remain to be elucidated and nothing is known about the potential effect of vitamin D analogues. Here we systematically investigate the effect of vitamin D and therapeutically used analogues (maxacalcitol, calcipotriol, alfacalcidol, paricalcitol, doxercalciferol) on AD-relevant mechanisms. D₂ and D₃ analogues decreased Aβ-production and increased Aβ-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the Aβ-producing Enzymes BACE1 and γ-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the γ-secretase. Vitamin D and analogues decreased β-secretase activity, not only in mouse brains with mild vitamin D hypovitaminosis, but also in non-deficient mouse brains. Our results further strengthen the link between AD and vitamin D, suggesting that supplementation of vitamin D or vitamin D analogues might have beneficial effects in AD prevention.

Keywords
Aβ-degradation; amyloid precursor protein; amyloid-β; secretases; vitamin D; vitamin D analogues.
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