Dataset Information

Vitamin D and Its Analogues Decrease Amyloid-? (A?) Formation and Increase A?-Degradation.

ABSTRACT: Alzheimer's disease (AD) is characterized by extracellular plaques in the brain, mainly consisting of amyloid-? (A?), 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?-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? and D? analogues decreased A?-production and increased A?-degradation in neuroblastoma cells or vitamin D deficient mouse brains. Effects were mediated by affecting the A?-producing enzymes BACE1 and ?-secretase. A reduced secretase activity was accompanied by a decreased BACE1 protein level and nicastrin expression, an essential component of the ?-secretase. Vitamin D and analogues decreased ?-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.

SUBMITTER: Grimm MOW

PROVIDER: S-EPMC5751363 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Grimm Marcus O W MOW Thiel Andrea A Lauer Anna A AA Winkler Jakob J Lehmann Johannes J Regner Liesa L Nelke Christopher C Janitschke Daniel D Benoist Céline C Streidenberger Olga O Stötzel Hannah H Endres Kristina K Herr Christian C Beisswenger Christoph C Grimm Heike S HS Bals Robert R Lammert Frank F Hartmann Tobias T

International journal of molecular sciences 20171219 12

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 poten ...[more]

PMID: 29257109

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Project description:Chaperones safeguard protein homeostasis by promoting folding and preventing aggregation. HSP110 is a cytosolic chaperone that functions as a nucleotide exchange factor for the HSP70 cycle. Together with HSP70 and a J-domain protein (JDP), HSP110 maintains protein folding and resolubilizes aggregates. Interestingly, HSP110 is vital for the HSP70/110/JDP-mediated disaggregation of amyloidogenic proteins implicated in neurodegenerative diseases (i.e., α-synuclein, HTT, and tau). However, despite its abundance, HSP110 remains still an enigmatic chaperone, and its functional spectrum is not very well understood. Of note, the disaggregation activity of neurodegenerative disease-associated amyloid fibrils showed both beneficial and detrimental outcomes in vivo. To gain a more comprehensive understanding of the chaperone HSP110 in vivo, we analyzed its role in neuronal proteostasis and neurodegeneration in C. elegans. Specifically, we investigated the role of HSP110 in the regulation of amyloid beta peptide (Aβ) aggregation using an established Aβ-C. elegans model that mimics Alzheimer's disease pathology. We generated a novel C. elegans model that over-expresses hsp-110 pan-neuronally, and we also depleted hsp-110 by RNAi-mediated knockdown. We assessed Aβ aggregation in vivo and in situ by fluorescence lifetime imaging. We found that hsp-110 over-expression exacerbated Aβ aggregation and appeared to reduce the conformational variability of the Aβ aggregates, whereas hsp-110 depletion reduced aggregation more significantly in the IL2 neurons, which marked the onset of Aβ aggregation. HSP-110 also plays a central role in growth and fertility as its over-expression compromises nematode physiology. In addition, we found that HSP-110 modulation affects the autophagy pathway. While hsp-110 over-expression impairs the autophagic flux, a depletion enhances it. Thus, HSP-110 regulates multiple nodes of the proteostasis network to control amyloid protein aggregation, disaggregation, and autophagic clearance.

Dataset Information

Vitamin D and Its Analogues Decrease Amyloid-? (A?) Formation and Increase A?-Degradation.

Publications

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

Similar Datasets

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