Vitamin D and Its Analogues Decrease Amyloid-β (Aβ) Formation and Increase Aβ-Degradation.
Marcus Otto Walter GrimmAndrea ThielAnna Andrea LauerJakob WinklerJohannes LehmannLiesa RegnerChristopher NelkeDaniel JanitschkeCéline BenoistOlga StreidenbergerHannah StötzelKristina EndresChristian HerrChristoph BeisswengerHeike S GrimmRobert BalsFrank LammertTobias HartmannPublished in: International journal of molecular sciences (2017)
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.
Keyphrases
- molecular docking
- cell death
- induced apoptosis
- end stage renal disease
- risk assessment
- small molecule
- climate change
- brain injury
- oxidative stress
- white matter
- binding protein
- peritoneal dialysis
- patient reported outcomes
- long non coding rna
- molecular dynamics
- prognostic factors
- density functional theory
- human health
- transcription factor
- cerebral ischemia
- pi k akt