65 research outputs found
The Impact of Vitamin E and Other Fat-Soluble Vitamins on Alzheimer´s Disease
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly population, currently affecting 46 million people worldwide. Histopathologically, the disease is characterized by the occurrence of extracellular amyloid plaques composed of aggregated amyloid-β (Aβ) peptides and intracellular neurofibrillary tangles containing the microtubule-associated protein tau. Aβ peptides are derived from the sequential processing of the amyloid precursor protein (APP) by enzymes called secretases, which are strongly influenced by the lipid environment. Several vitamins have been reported to be reduced in the plasma/serum of AD-affected individuals indicating they have an impact on AD pathogenesis. In this review we focus on vitamin E and the other lipophilic vitamins A, D, and K, and summarize the current knowledge about their status in AD patients, their impact on cognitive functions and AD risk, as well as their influence on the molecular mechanisms of AD. The vitamins might affect the generation and clearance of Aβ both by direct effects and indirectly by altering the cellular lipid homeostasis. Additionally, vitamins A, D, E, and K are reported to influence further mechanisms discussed to be involved in AD pathogenesis, e.g., Aβ-aggregation, Aβ-induced neurotoxicity, oxidative stress, and inflammatory processes, as summarized in this article
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
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
Plasmalogens Inhibit APP Processing by Directly Affecting γ-Secretase Activity in Alzheimer's Disease
Lipids play an important role as risk or protective factors in Alzheimer's disease (AD). Previously it has been shown that plasmalogens, the major brain phospholipids, are altered in AD. However, it remained unclear whether plasmalogens themselves are able to modulate amyloid precursor protein (APP) processing or if the reduced plasmalogen level is a consequence of AD. Here we identify the plasmalogens which are altered in human AD postmortem brains and investigate their impact on APP processing resulting in Aβ production. All tested plasmalogen species showed a reduction in γ-secretase activity whereas β- and α-secretase activity mainly remained unchanged. Plasmalogens directly affected γ-secretase activity, protein and RNA level of the secretases were unaffected, pointing towards a direct influence of plasmalogens on γ-secretase activity. Plasmalogens were also able to decrease γ-secretase activity in human postmortem AD brains emphasizing the impact of plasmalogens in AD. In summary our findings show that decreased plasmalogen levels are not only a consequence of AD but that plasmalogens also decrease APP processing by directly affecting γ-secretase activity, resulting in a vicious cycle: Aβ reduces plasmalogen levels and reduced plasmalogen levels directly increase γ-secretase activity leading to an even stronger production of Aβ peptides
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
Intracellular APP Domain Regulates Serine-Palmitoyl-CoA Transferase Expression and Is Affected in Alzheimer's Disease
Lipids play an important role as risk or protective factors in Alzheimer's disease (AD), a disease biochemically characterized by the accumulation of amyloid beta peptides (Aβ), released by proteolytic processing of the amyloid precursor protein (APP). Changes in sphingolipid metabolism have been associated to the development of AD. The key enzyme in sphingolipid de novo synthesis is serine-palmitoyl-CoA transferase (SPT). In the present study we identified a new physiological function of APP in sphingolipid synthesis. The APP intracellular domain (AICD) was found to decrease the expression of the SPT subunit SPTLC2, the catalytic subunit of the SPT heterodimer, resulting in that decreased SPT activity. AICD function was dependent on Fe65 and SPTLC2 levels are increased in APP knock-in mice missing a functional AICD domain. SPTLC2 levels are also increased in familial and sporadic AD postmortem brains, suggesting that SPT is involved in AD pathology
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
Regulatory feedback cycle of the insulin-degrading enzyme and the amyloid precursor protein intracellular domain: Implications for Alzheimer's disease
One of the major pathological hallmarks of Alzheimer´s disease (AD) is an accumulation of amyloid-β (Aβ) in brain tissue leading to formation of toxic oligomers and senile plaques. Under physiological conditions, a tightly balanced equilibrium between Aβ-production and -degradation is necessary to prevent pathological Aβ-accumulation. Here, we investigate the molecular mechanism how insulin-degrading enzyme (IDE), one of the major Aβ-degrading enzymes, is regulated and how amyloid precursor protein (APP) processing and Aβ-degradation is linked in a regulatory cycle to achieve this balance. In absence of Aβ-production caused by APP or Presenilin deficiency, IDE-mediated Aβ-degradation was decreased, accompanied by a decreased IDE activity, protein level, and expression. Similar results were obtained in cells only expressing a truncated APP, lacking the APP intracellular domain (AICD) suggesting that AICD promotes IDE expression. In return, APP overexpression mediated an increased IDE expression, comparable results were obtained with cells overexpressing C50, a truncated APP representing AICD. Beside these genetic approaches, also AICD peptide incubation and pharmacological inhibition of the γ-secretase preventing AICD production regulated IDE expression and promoter activity. By utilizing CRISPR/Cas9 APP and Presenilin knockout SH-SY5Y cells results were confirmed in a second cell line in addition to mouse embryonic fibroblasts. In vivo, IDE expression was decreased in mouse brains devoid of APP or AICD, which was in line with a significant correlation of APP expression level and IDE expression in human postmortem AD brains. Our results show a tight link between Aβ-production and Aβ-degradation forming a regulatory cycle in which AICD promotes Aβ-degradation via IDE and IDE itself limits its own production by degrading AICD
Tocotrienol Affects Oxidative Stress, Cholesterol Homeostasis and the Amyloidogenic Pathway in Neuroblastoma Cells: Consequences for Alzheimer’s Disease
One of the characteristics of Alzheimer´s disease (AD) is an increased amyloid load and an enhanced level of reactive oxidative species (ROS). Vitamin E has known beneficial neuroprotective effects, and previously, some studies suggested that vitamin E is associated with a reduced risk of AD due to its antioxidative properties. However, epidemiological studies and nutritional approaches of vitamin E treatment are controversial. Here, we investigate the effect of α-tocotrienol, which belongs to the group of vitamin E, on AD-relevant processes in neuronal cell lines. In line with the literature, α-tocotrienol reduced the ROS level in SH-SY5Y cells. In the presence of tocotrienols, cholesterol and cholesterol esters, which have been shown to be risk factors in AD, were decreased. Besides the unambiguous positive effects of tocotrienol, amyloid-β (Aβ) levels were increased accompanied by an increase in the activity of enzymes responsible for Aβ production. Proteins and gene expression of the secretases and their components remained unchanged, whereas tocotrienol accelerates enzyme activity in cell-free assays. Besides enhanced Aβ production, tocotrienols inhibited Aβ degradation in neuro 2a (N2a)-cells. Our results might help to understand the controversial findings of vitamin E studies and demonstrate that besides the known positive neuroprotective properties, tocotrienols also have negative characteristics with respect to AD
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