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Int. J. Mol. Sci. 2017, 18(12), 2764; https://doi.org/10.3390/ijms18122764

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

1
Experimental Neurology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany
2
Neurodegeneration and Neurobiology, Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany
3
Deutsches Institut für DemenzPrävention (DIDP), Saarland University, Kirrberger Str. 1, 66421 Homburg/Saar, Germany
4
Department of Internal Medicine II–Gastroenterology, Saarland University Hospital, Saarland University, Kirrberger Str. 100, 66421 Homburg/Saar, Germany
5
Department of Psychiatry and Psychotherapy, Clinical Research Group, University Medical Centre Johannes Gutenberg, University of Mainz, Untere Zahlbacher Str. 8, 55131 Mainz, Germany
6
Department of Internal Medicine V–Pulmonology, Allergology, Respiratory Intensive Care Medicine, Saarland University Hospital, Kirrberger Str. 1, 66421 Homburg/Saar, Germany
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 3 November 2017 / Revised: 1 December 2017 / Accepted: 13 December 2017 / Published: 19 December 2017
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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. View Full-Text
Keywords: vitamin D; vitamin D analogues; amyloid precursor protein; amyloid-β; secretases; Aβ-degradation vitamin D; vitamin D analogues; amyloid precursor protein; amyloid-β; secretases; Aβ-degradation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Grimm, M.O.W.; Thiel, A.; Lauer, A.A.; Winkler, J.; Lehmann, J.; Regner, L.; Nelke, C.; Janitschke, D.; Benoist, C.; Streidenberger, O.; Stötzel, H.; Endres, K.; Herr, C.; Beisswenger, C.; Grimm, H.S.; Bals, R.; Lammert, F.; Hartmann, T. Vitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation. Int. J. Mol. Sci. 2017, 18, 2764.

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