Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 18, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/ijms18122764
Keywords
vitamin D; vitamin D analogues; amyloid precursor protein; amyloid-beta; secretases; A beta-degradation
Funding
- EU project LipiDiDiet [211696]
- Fundacio la Marato de TV3 [20140931]
- JPND (EU Joint Programme-Neurodegenerative Disease Research) [Mind AD 1ED1508]
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Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-beta (A beta), 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 A beta-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. D-2 and D-3 analogues decreased A beta-production and increased A beta-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the A beta-producing enzymes BACE1 and gamma-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the gamma-secretase. Vitamin D and analogues decreased beta-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.
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