98 research outputs found
The Effects of Vitamin D Deficiency on Neurodegenerative Diseases
Approximately 90% of the elderly population in the western countries has at least a mild to moderate vitamin D hypovitaminosis. Besides the well-known function of vitamin D in calcium homeostasis, it has been recently found that several enzymes and receptors involved in its homeostasis are expressed in the nervous system and brain suggesting also an important role in the brain homeostasis. Interestingly, epidemiological and clinical studies found reduced vitamin D level associated with an increased risk of several neurodegenerative disorders. In this chapter, we focus on a potential link between vitamin D and Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, prion disease, and motor neuron disease. Epidemiological studies were summarized, an overview of the known potential underlying pathomolecular mechanisms are given, and results from clinical studies dealing with vitamin D supplementation were presented. As an outlook, recent literature suggesting an impact of vitamin D on autism spectrum disease, depression, and schizophrenia are briefly discussed. In conclusion, the identification of an abundant vitamin D metabolism in the brain and the tight link between the increasing number of several neurological and mental disorders emphasize the need of further research making a clear recommendation of the intake and supplementation of vitamin D in a growing elderly population
Methylxanthines and Neurodegenerative Diseases: An Update
Methylxanthines (MTX) are purine derived xanthine derivatives. Whereas naturally
occurring methylxanthines like caffeine, theophylline or theobromine are widely consumed in food,
several synthetic but also non-synthetic methylxanthines are used as pharmaceuticals, in particular in
treating airway constrictions. Besides the well-established bronchoprotective effects, methylxanthines
are also known to have anti-inflammatory and anti-oxidative properties, mediate changes in lipid
homeostasis and have neuroprotective effects. Known molecular mechanisms include adenosine
receptor antagonism, phosphodiesterase inhibition, effects on the cholinergic system, wnt signaling,
histone deacetylase activation and gene regulation. By affecting several pathways associated with
neurodegenerative diseases via different pleiotropic mechanisms and due to its moderate side
effects, intake of methylxanthines have been suggested to be an interesting approach in dealing with
neurodegeneration. Especially in the past years, the impact of methylxanthines in neurodegenerative
diseases has been extensively studied and several new aspects have been elucidated. In this review
we summarize the findings of methylxanthines linked to Alzheimer´s disease, Parkinson’s disease
and Multiple Sclerosis since 2017, focusing on epidemiological and clinical studies and addressing
the underlying molecular mechanisms in cell culture experiments and animal studies in order to
assess the neuroprotective potential of methylxanthines in these diseases
Development of an autonomous mobile towing vehicle for logistic tasks
Frequently carrying high loads and performing repetitive
tasks compromises the ergonomics of individuals, a recurrent scenario
in hospital environments. In this paper, we design a logistic planner of
a fleet of autonomous mobile robots for the automation of transporting
trolleys around the hospital, which is independent of the space configuration,
and robust to loss of network and deadlocks. Our robotic solution
has an innovative gripping system capable of grasping and pulling nonmodified
standard trolleys just by coupling a plate. Robots are able to
navigate autonomously, to avoid obstacles assuring the safety of operators,
to identify and dock a trolley, to access charging stations and
elevators, and to communicate with the latter. An interface was built
allowing users to command the robots through a web server. It is shown
how the proposed methodology behaves in experiments conducted at the
Faculty of Engineering of the University of Porta and Braga's Hospital.This work is financed by the ERDF - European Regional
Development Fund through the Operational Programme for Competitiveness and Internationalisation-
COMPETE 2020 Programme, and by National Funds through the Portuguese
funding agency, FCT-Fundação para a Ciência e a Tecnologia, within project
SAICTPAC/0034/2015 - POCI-01- 0145-FEDER-016418.
Authors would like to acknowledge to Trivalor, Itau and Gertal for the support of
the project RDH.info:eu-repo/semantics/publishedVersio
Unique Role of Caffeine Compared to Other Methylxanthines (Theobromine, Theophylline, Pentoxifylline, Propentofylline) in Regulation of AD Relevant Genes in Neuroblastoma SH-SY5Y Wild Type Cells
Methylxanthines are a group of substances derived from the purine base xanthine with
a methyl group at the nitrogen on position 3 and different residues at the nitrogen on position 1
and 7. They are widely consumed in nutrition and used as pharmaceuticals. Here we investigate
the transcriptional regulation of 83 genes linked to Alzheimer’s disease in the presence of five
methylxanthines, including the most prominent naturally occurring methylxanthines—caffeine,
theophylline and theobromine—and the synthetic methylxanthines pentoxifylline and propentofylline.
Methylxanthine-regulated genes were found in pathways involved in processes including oxidative
stress, lipid homeostasis, signal transduction, transcriptional regulation, as well as pathways involved
in neuronal function. Interestingly, multivariate analysis revealed different or inverse effects on gene
regulation for caffeine compared to the other methylxanthines, which was further substantiated by
multiple comparison analysis, pointing out a distinct role for caffeine in gene regulation. Our results
not only underline the beneficial effects of methylxanthines in the regulation of genes in neuroblastoma
wild-type cells linked to neurodegenerative diseases in general, but also demonstrate that individual
methylxanthines like caffeine mediate unique or inverse expression patterns. This suggests that the
replacement of single methylxanthines by others could result in unexpected effects, which could not
be anticipated by the comparison to other substances in this substance class
The impact of capsaicinoids on APP processing in Alzheimer's disease in SH-SY5Y cells
The vanilloid capsaicin is a widely consumed spice, known for its burning and "hot" sensation through activation of TRPV1 ion-channels, but also known to decrease oxidative stress, inflammation and influence tau-pathology. Beside these positive effects, little is known about its effects on amyloid-precursor-protein (APP) processing leading to amyloid-β (Aβ), the major component of senile plaques. Treatment of neuroblastoma cells with capsaicinoids (24 hours, 10 µM) resulted in enhanced Aβ-production and reduced Aβ-degradation, leading to increased Aβ-levels. In detailed analysis of the amyloidogenic-pathway, both BACE1 gene-expression as well as protein-levels were found to be elevated, leading to increased β-secretase-activity. Additionally, γ-secretase gene-expression as well as activity was enhanced, accompanied by a shift of presenilin from non-raft to raft membrane-domains where amyloidogenic processing takes place. Furthermore, impaired Aβ-degradation in presence of capsaicinoids is dependent on the insulin-degrading-enzyme, one of the major Aβ-degrading-enzymes. Regarding Aβ-homeostasis, no differences were found between the major capsaicinoids, capsaicin and dihydrocapsaicin, and a mixture of naturally derived capsaicinoids; effects on Ca2+-homeostasis were ruled out. Our results show that in respect to Alzheimer's disease, besides the known positive effects of capsaicinoids, pro-amyloidogenic properties also exist, enhancing Aβ-levels, likely restricting the potential use of capsaicinoids as therapeutic substances in Alzheimer's disease
A short isoform of STIM1 confers frequency-dependent synaptic enhancement
Store-operated Ca2+-entry (SOCE) regulates basal and receptor-triggered Ca2+ signaling with STIM proteins
sensing the endoplasmic reticulum (ER) Ca2+ content and triggering Ca2+ entry by gating Orai channels.
Although crucial for immune cells, STIM1’s role in neuronal Ca2+ homeostasis is controversial. Here, we
characterize a splice variant, STIM1B, which shows exclusive neuronal expression and protein content surpassing conventional STIM1 in cerebellum and of significant abundance in other brain regions. STIM1B
expression results in a truncated protein with slower kinetics of ER-plasma membrane (PM) cluster formation
and ICRAC, as well as reduced inactivation. In primary wild-type neurons, STIM1B is targeted by its spliced-in
domain B to presynaptic sites where it converts classic synaptic depression into Ca2+- and Orai-dependent
short-term synaptic enhancement (STE) at high-frequency stimulation (HFS). In conjunction with altered
STIM1 splicing in human Alzheimer disease, our findings highlight STIM1 splicing as an important regulator
of neuronal calcium homeostasis and of synaptic plasticity
Medium-Chain Length Fatty Acids Enhance Aβ Degradation by Affecting Insulin-Degrading Enzyme
The accumulation of amyloid β-protein (Aβ) is one of the major pathological hallmarks
of Alzheimer’s disease. Insulin-degrading enzyme (IDE), a zinc-metalloprotease, is a key enzyme
involved in Aβ degradation, which, in addition to Aβ production, is critical for Aβ homeostasis. Here,
we demonstrate that saturated medium-chain fatty acids (MCFAs) increase total Aβ degradation
whereas longer saturated fatty acids result in an inhibition of its degradation, an effect which
could not be detected in IDE knock-down cells. Further analysis of the underlying molecular
mechanism revealed that MCFAs result in an increased exosomal IDE secretion, leading to an
elevated extracellular and a decreased intracellular IDE level whereas gene expression of IDE was
unaffected in dependence of the chain length. Additionally, MCFAs directly elevated the enzyme
activity of recombinant IDE, while longer-chain length fatty acids resulted in an inhibited IDE activity.
The effect of MCFAs on IDE activity could be confirmed in mice fed with a MCFA-enriched diet,
revealing an increased IDE activity in serum. Our data underline that not only polyunsaturated
fatty acids such as docosahexaenoic acid (DHA), but also short-chain fatty acids, highly enriched, for
example in coconut oil, might be beneficial in preventing or treating Alzheimer’s disease
The Influence of Acitretin on Brain Lipidomics in Adolescent Mice : Implications for Pediatric and Adolescent Dermatological Therapy
Administration of systemic retinoids such as acitretin has not been approved yet for
pediatric patients. An adverse event of retinoid-therapy that occurs with lower prevalence in children
than in adults is hyperlipidemia. This might be based on the lack of comorbidities in young patients,
but must not be neglected. Especially for the development of the human brain up to young adulthood,
dysbalance of lipids might be deleterious. Here, we provide for the first time an in-depth analysis
of the influence of subchronic acitretin-administration on lipid composition of brain parenchyma of
young wild type mice. For comparison and to evaluate the systemic effect of the treatment, liver lipids
were analogously investigated. As expected, triglycerides increased in liver as well as in brain and a
non-significant increase in cholesterol was observed. However, specifically brain showed an increase
in lyso-phosphatidylcholine and carnitine as well as in sphingomyelin. Group analysis of lipid
classes revealed no statistical effects, while single species were tissue-dependently changed: effects
in brain were in general more subtly as compared to those in liver regarding the mere number of
changed lipid species. Thus, while the overall impact of acitretin seems comparably small regarding
brain, the change in individual species and their role in brain development and maturation has to
be considered
Mechanistic Link between Vitamin B12 and Alzheimer’s Disease
Alzheimer’s disease (AD) is the most common form of dementia in the elderly population,
affecting over 55 million people worldwide. Histopathological hallmarks of this multifactorial disease
are an increased plaque burden and tangles in the brains of affected individuals. Several lines of
evidence indicate that B12 hypovitaminosis is linked to AD. In this review, the biochemical pathways
involved in AD that are affected by vitamin B12, focusing on APP processing, Aβ fibrillization, Aβ induced oxidative damage as well as tau hyperphosphorylation and tau aggregation, are summarized.
Besides the mechanistic link, an overview of clinical studies utilizing vitamin B supplementation are
given, and a potential link between diseases and medication resulting in a reduced vitamin B12 level
and AD are discussed. Besides the disease-mediated B12 hypovitaminosis, the reduction in vitamin
B12 levels caused by an increasing change in dietary preferences has been gaining in relevance. In
particular, vegetarian and vegan diets are associated with vitamin B12 deficiency, and therefore
might have potential implications for AD. In conclusion, our review emphasizes the important role
of vitamin B12 in AD, which is particularly important, as even in industrialized countries a large
proportion of the population might not be sufficiently supplied with vitamin B12
Shotgun lipidomics of liver and brain tissue of Alzheimer's disease model mice treated with acitretin
Alzheimer’s disease (AD) is a very frequent neurodegenerative disorder characterized by an accumulation of amyloid-β (Aβ). Acitretin, a retinoid-derivative and approved treatment for Psoriasis vulgaris, increases non-amyloidogenic Amyloid-Precursor-Protein-(APP)-processing, prevents Aβ-production and elicits cognitive improvement in AD mouse models. As an unintended side effect, acitretin could result in hyperlipidemia. Here, we analyzed the impact of acitretin on the lipidome in brain and liver tissue in the 5xFAD mouse-model. In line with literature, triglycerides were increased in liver accompanied by increased PCaa, plasmalogens and acyl-carnitines, whereas SM-species were decreased. In brain, these effects were partially enhanced or similar but also inverted. While for SM and plasmalogens similar effects were found, PCaa, TAG and acyl-carnitines showed an inverse effect in both tissues. Our findings emphasize, that potential pharmaceuticals to treat AD should be carefully monitored with respect to lipid-homeostasis because APP-processing itself modulates lipid-metabolism and medication might result in further and unexpected changes. Moreover, deducing effects of brain lipid-homeostasis from results obtained for other tissues should be considered cautiously. With respect to acitretin, the increase in brain plasmalogens might display a further positive probability in AD-treatment, while other results, such as decreased SM, indicate the need of medical surveillance for treated patients
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