Gemfibrozil-Induced Intracellular Triglyceride Increase in SH-SY5Y, HEK and Calu-3 Cells

Gemfibrozil is a drug that has been used for over 40 years to lower triglycerides in blood. As a ligand for peroxisome proliferative-activated receptor-alpha (PPARα), which is expressed in many tissues, it induces the transcription of numerous genes for carbohydrate and lipid-metabolism. However, nothing is known about how intracellular lipid-homeostasis and, in particular, triglycerides are affected. As triglycerides are stored in lipid-droplets, which are known to be associated with many diseases, such as Alzheimer’s disease, cancer, fatty liver disease and type-2 diabetes, treatment with gemfibrozil could adversely affect these diseases. To address the question whether gemfibrozil also affects intracellular lipid-levels, SH-SY5Y, HEK and Calu-3 cells, representing three different metabolically active organs (brain, lung and kidney), were incubated with gemfibrozil and subsequently analyzed semi-quantitatively by mass-spectrometry. Importantly, all cells showed a strong increase in intracellular triglycerides (SH-SY5Y: 170.3%; HEK: 272.1%; Calu-3: 448.1%), suggesting that the decreased triglyceride-levels might be due to an enhanced cellular uptake. Besides the common intracellular triglyceride increase, a cell-line specific alteration in acylcarnitines are found, suggesting that especially in neuronal cell lines gemfibrozil increases the transport of fatty acids to mitochondria and therefore increases the turnover of fatty acids for the benefit of additional energy supply, which could be important in diseases, such as Alzheimer’s disease

Vitamin D and Its Analogues: From Differences in Molecular Mechanisms to Potential Benefits of Adapted Use in the Treatment of Alzheimer’s Disease

Lifestyle habits and insufficient sunlight exposure lead to a high prevalence of vitamin D hypovitaminosis, especially in the elderly. Recent studies suggest that in central Europe more than 50% of people over 60 years are not sufficiently supplied with vitamin D. Since vitamin D hypovitaminosis is associated with many diseases, such as Alzheimer’s disease (AD), vitamin D supplementation seems to be particularly useful for this vulnerable age population. Importantly, in addition to vitamin D, several analogues are known and used for different medical purposes. These vitamin D analogues differ not only in their pharmacokinetics and binding affinity to the vitamin D receptor, but also in their potential side effects. Here, we discuss these aspects, especially those of the commonly used vitamin D analogues alfacalcidol, paricalcitol, doxercalciferol, tacalcitol, calcipotriol, and eldecalcitol. In addition to their pleiotropic effects on mechanisms relevant to AD, potential effects of vitamin D analogues on comorbidities common in the context of geriatric diseases are summarized. AD is defined as a complex neurodegenerative disease of the central nervous system and is commonly represented in the elderly population. It is usually caused by extracellular accumulation of amyloidogenic plaques, consisting of amyloid (Aβ) peptides. Furthermore, the formation of intracellular neurofibrillary tangles involving hyperphosphorylated tau proteins contributes to the pathology of AD. In conclusion, this review emphasizes the importance of an adequate vitamin D supply and discusses the specifics of administering various vitamin D analogues compared with vitamin D in geriatric patients, especially those suffering from AD

Interprofessional education: a necessity in Alzheimer’s dementia care—a pilot study

Introduction: Interprofessional collaboration is seen as an indispensable prerequisite for high-quality health services and patient care, especially for complex diseases such as dementia. Thus, the current project aimed to extend interprofessional and competency-based education in the field of dementia care to the previously understudied therapy professions of nutrition, speech-language pathology, and physiotherapy. Methods: A three-day workshop was designed to provide specific learning objectives related to patient-centered dementia care, as well as competences for interprofessional collaboration. Teaching and learning approaches included case-based learning in simulated interprofessional case-conferences and peerteaching. A total of 42 students (n  =  20 nutrition therapy and counseling, n  =  8 speech-language pathology, n  =  14 physiotherapy), ranging from first to seventh semester, finished the whole workshop and were considered in data analysis. Changes in self-perceived attitudes toward interprofessional collaboration and education were measured by the German version of the UWE-IP. An in-house questionnaire was developed to evaluate knowledge and skills in the field of dementia, dementia management and interprofessional collaboration. Results: Participation in the workshop led to significant improvements in the total scores of the UWE-IP-D and the in-house questionnaire, as well as their respective subscales. Moderate to large effect sizes were achieved. All professions improved significantly in both questionnaires with large effect sizes. Significant differences between professions were found in the UWE-IP-D total score between students of speech-language pathology and physiotherapy in the posttest. Students of nutrition therapy and counseling revealed a significant lower level of self-perceived knowledge and skills in the in-house questionnaire pre- and post-testing. Discussion: The pilot-study confirms the effectiveness of interprofessional education to promote generic and interprofessional dementia care competencies and to develop positive attitudes toward interprofessional learning and collaboration in the therapy professions, thus increasing professional diversity in interprofessional education research. Differences between professions were confounded by heterogenous semester numbers and participation conditions. To achieve a curricular implementation, interprofessional education should be expanded to include a larger group of participants belonging to different professions, start early in the study program, and be evaluated over the long term

Effect of Caffeine and Other Methylxanthines on Aβ-Homeostasis in SH-SY5Y Cells

Methylxanthines (MTX) are alkaloids derived from the purine-base xanthine. Whereas especially caffeine, the most prominent known MTX, has been formerly assessed to be detrimental, this point of view has changed substantially. MTXs are discussed to have beneficial properties in neurodegenerative diseases, however, the mechanisms of action are not completely understood. Here we investigate the effect of the naturally occurring caffeine, theobromine and theophylline and the synthetic propentofylline and pentoxifylline on processes involved in Alzheimer’s disease (AD). All MTXs decreased amyloid-β (Aβ) level by shifting the amyloid precursor protein (APP) processing from the Aβ-producing amyloidogenic to the non-amyloidogenic pathway. The α-secretase activity was elevated whereas β-secretase activity was decreased. Breaking down the molecular mechanism, caffeine increased protein stability of the major α-secretase ADAM10, downregulated BACE1 expression and directly decreased β-secretase activity. Additionally, APP expression was reduced. In line with literature, MTXs reduced oxidative stress, decreased cholesterol and a decreased in Aβ1-42 aggregation. In conclusion, all MTXs act via the pleiotropic mechanism resulting in decreased Aβ and show beneficial properties with respect to AD in neuroblastoma cells. However, the observed effect strength was moderate, suggesting that MTXs should be integrated in a healthy diet rather than be used exclusively to treat or prevent AD

Interprofessional education: a necessity in Alzheimer’s dementia care—a pilot study

IntroductionInterprofessional collaboration is seen as an indispensable prerequisite for high-quality health services and patient care, especially for complex diseases such as dementia. Thus, the current project aimed to extend interprofessional and competency-based education in the field of dementia care to the previously understudied therapy professions of nutrition, speech-language pathology, and physiotherapy.MethodsA three-day workshop was designed to provide specific learning objectives related to patient-centered dementia care, as well as competences for interprofessional collaboration. Teaching and learning approaches included case-based learning in simulated interprofessional case-conferences and peer-teaching. A total of 42 students (n = 20 nutrition therapy and counseling, n = 8 speech-language pathology, n = 14 physiotherapy), ranging from first to seventh semester, finished the whole workshop and were considered in data analysis. Changes in self-perceived attitudes toward interprofessional collaboration and education were measured by the German version of the UWE-IP. An in-house questionnaire was developed to evaluate knowledge and skills in the field of dementia, dementia management and interprofessional collaboration.ResultsParticipation in the workshop led to significant improvements in the total scores of the UWE-IP-D and the in-house questionnaire, as well as their respective subscales. Moderate to large effect sizes were achieved. All professions improved significantly in both questionnaires with large effect sizes. Significant differences between professions were found in the UWE-IP-D total score between students of speech-language pathology and physiotherapy in the posttest. Students of nutrition therapy and counseling revealed a significant lower level of self-perceived knowledge and skills in the in-house questionnaire pre- and post-testing.DiscussionThe pilot-study confirms the effectiveness of interprofessional education to promote generic and interprofessional dementia care competencies and to develop positive attitudes toward interprofessional learning and collaboration in the therapy professions, thus increasing professional diversity in interprofessional education research. Differences between professions were confounded by heterogenous semester numbers and participation conditions. To achieve a curricular implementation, interprofessional education should be expanded to include a larger group of participants belonging to different professions, start early in the study program, and be evaluated over the long term

Interdisciplinary Approaches to Deal with Alzheimer’s Disease : From Bench to Bedside: What Feasible Options Do Already Exist Today?

Alzheimer’s disease is one of the most common neurodegenerative diseases in the western population. The incidence of this disease increases with age. Rising life expectancy and the resulting increase in the ratio of elderly in the population are likely to exacerbate socioeconomic problems. Alzheimer’s disease is a multifactorial disease. In addition to amyloidogenic processing leading to plaques, and tau pathology, but also other molecular causes such as oxidative stress or inflammation play a crucial role. We summarize the molecular mechanisms leading to Alzheimer’s disease and which potential interventions are known to interfere with these mechanisms, focusing on nutritional approaches and physical activity but also the beneficial effects of cognition-oriented treatments with a focus on language and communication. Interestingly, recent findings also suggest a causal link between oral conditions, such as periodontitis or edentulism, and Alzheimer’s disease, raising the question of whether dental intervention in Alzheimer’s patients can be beneficial as well. Unfortunately, all previous single-domain interventions have been shown to have limited benefit to patients. However, the latest studies indicate that combining these efforts into multidomain approaches may have increased preventive or therapeutic potential. Therefore, as another emphasis in this review, we provide an overview of current literature dealing with studies combining the above-mentioned approaches and discuss potential advantages compared to monotherapies. Considering current literature and intervention options, we also propose a multidomain interdisciplinary approach for the treatment of Alzheimer’s disease patients that synergistically links the individual approaches. In conclusion, this review highlights the need to combine different approaches in an interdisciplinary manner, to address the future challenges of Alzheimer’s disease

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

Methylxanthines Induce a Change in the AD/Neurodegeneration-Linked Lipid Profile in Neuroblastoma Cells

Alzheimer’s disease (AD) is characterized by an increased plaque burden and tangle accumulation in the brain accompanied by extensive lipid alterations. Methylxanthines (MTXs) are alkaloids frequently consumed by dietary intake known to interfere with the molecular mechanisms leading to AD. Besides the fact that MTX consumption is associated with changes in triglycerides and cholesterol in serum and liver, little is known about the effect of MTXs on other lipid classes, which raises the question of whether MTX can alter lipids in a way that may be relevant in AD. Here we have analyzed naturally occurring MTXs caffeine, theobromine, theophylline, and the synthetic MTXs pentoxifylline and propentofylline also used as drugs in different neuroblastoma cell lines. Our results show that lipid alterations are not limited to triglycerides and cholesterol in the liver and serum, but also include changes in sphingomyelins, ceramides, phosphatidylcholine, and plasmalogens in neuroblastoma cells. These changes comprise alterations known to be beneficial, but also adverse effects regarding AD were observed. Our results give an additional perspective of the complex link between MTX and AD, and suggest combining MTX with a lipid-altering diet compensating the adverse effects of MTX rather than using MTX alone to prevent or treat AD

Targeted Lipidomics of Mitochondria in a Cellular Alzheimer’s Disease Model

Alzheimer’s disease (AD) is neuropathologically characterized by the accumulation of Amyloid-β (Aβ) in senile plaques derived from amyloidogenic processing of a precursor protein (APP). Recently, changes in mitochondrial function have become in the focus of the disease. Whereas a link between AD and lipid-homeostasis exists, little is known about potential alterations in the lipid composition of mitochondria. Here, we investigate potential changes in the main mitochondrial phospholipid classes phosphatidylcholine, phosphatidylethanolamine and the corresponding plasmalogens and lyso-phospholipids of a cellular AD-model (SH-SY5Y APPswedish transfected cells), comparing these results with changes in cell-homogenates. Targeted shotgun-lipidomics revealed lipid alterations to be specific for mitochondria and cannot be predicted from total cell analysis. In particular, lipids containing three and four times unsaturated fatty acids (FA X:4), such as arachidonic-acid, are increased, whereas FA X:6 or X:5, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), are decreased. Additionally, PE plasmalogens are increased in contrast to homogenates. Results were confirmed in another cellular AD model, having a lower affinity to amyloidogenic APP processing. Besides several similarities, differences in particular in PE species exist, demonstrating that differences in APP processing might lead to specific changes in lipid homeostasis in mitochondria. Importantly, the observed lipid alterations are accompanied by changes in the carnitine carrier system, also suggesting an altered mitochondrial functionalit

Vitamin B12 Attenuates Changes in Phospholipid Levels Related to Oxidative Stress in SH-SY5Y Cells

Oxidative stress is closely linked to Alzheimer’s disease (AD), and is detected peripherally as well as in AD-vulnerable brain regions. Oxidative stress results from an imbalance between the generation and degradation of reactive oxidative species (ROS), leading to the oxidation of proteins, nucleic acids, and lipids. Extensive lipid changes have been found in post mortem AD brain tissue; these changes include the levels of total phospholipids, sphingomyelin, and ceramide, as well as plasmalogens, which are highly susceptible to oxidation because of their vinyl ether bond at the sn-1 position of the glycerol-backbone. Several lines of evidence indicate that a deficiency in the neurotropic vitamin B12 is linked with AD. In the present study, treatment of the neuroblastoma cell line SH-SY5Y with vitamin B12 resulted in elevated levels of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and plasmalogens. Vitamin B12 also protected plasmalogens from hydrogen peroxide (H2O2 )-induced oxidative stress due to an elevated expression of the ROS-degrading enzymes superoxide-dismutase (SOD) and catalase (CAT). Furthermore, vitamin B12 elevates plasmalogen synthesis by increasing the expression of alkylglycerone phosphate synthase (AGPS) and choline phosphotransferase 1 (CHPT1) in SH-SY5Y cells exposed to H2O2 -induced oxidative stress