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

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 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

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

Response to: Commentary on “Surgical treatment of gynaecomastia: a standard of care in plastic surgery” by Alessandro Innocenti, Serena Ghezzi & Dario Melita.

<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>Severe hand injuries significantly limit function and esthetics of the affected hand due to massive trauma in skeletal and soft tissues. Surgical reconstruction is often unsatisfactory, so bionic prostheses are a consideration. However, assessment of functional outcomes and quality of life after surgical reconstruction to guide clinical decisions immediately after injury and in the course of treatment remain difficult.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>We conducted a prospective follow-up analysis of patients with severe hand injuries during 2016–2018. We retrospectively evaluated initial trauma severity and examined current functional status, quality of life, general function, and satisfaction in everyday situations of the hand. We also developed a novel Hand Bionic Score to guide clinical recommendation for selective amputation and bionic prosthesis supply.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>We examined 30 patients with a mean age of 53.8 years and mean initial severity of hand injury (iHISS) of 138.4. Measures indicated moderate quality of life limitations, moderate to severe limitation of overall hand function, and slight to moderate limitation of actual hand strength and function. Mean time to follow-up examination was 3.67 years. Using the measured outcomes, we developed a Hand Bionic Score that showed good ability to differentiate patients based on outcome markers. Appropriate cutoff scores for all measured outcome markers were used to determine Hand Bionic Score classifications to guide clinical recommendation for elective amputation and bionic prosthetic supply: < 10 points, bionic hand supply not recommended; 10–14, bionic supply should be considered; or > 14, bionic supply is recommended.</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>While iHISS can guide early clinical decisions following severe hand injury, our novel Hand Bionic Score provides orientation for clinical decision-making regarding elective amputation and bionic prosthesis supply later during the course of treatment. The score not only considers hand function but also psychological outcomes and quality of life, which are important considerations for patients with severe hand injuries. However, future randomized multicenter studies are needed to validate Hand Bionic Score before further clinical application.</jats:p> <jats:p>Level of evidence: Level III, risk/prognostic study.</jats:p> </jats:sec&gt

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

Influence of Tamoxifen on Different Biological Pathways in Tumorigenesis and Transformation in Adipose-Derived Stem Cells, Mammary Cells and Mammary Carcinoma Cell Lines—An In Vitro Study

Breast carcinoma is one of the most common malignant tumors in women. In cases of hormone-sensitive cells, tamoxifen as an anti-estrogenic substance is a first line medication in the adjuvant setting. The spectrum of autologous breast reconstructions ranges from fat infiltrations to complex microsurgical procedures. The influence of adipose-derived stem cells (ASC) on the tumor bed and a possibly increased recurrence rate as a result are critically discussed. In addition, there is currently no conclusive recommendation regarding tamoxifen-treated patients and autologous fat infiltrations. The aim of the present study was to investigate the effect of tamoxifen on the gene expression of a variety of genes involved in tumorigenesis, cell growth and transformation. Mammary epithelial cell line and mammary carcinoma cell lines were treated with tamoxifen in vitro as well as co-cultured with ASC. Gene expression was quantified by PCR arrays and showed increased expression in the mammary carcinoma cell lines with increasing time of treatment and concentration of tamoxifen. The data presented can be considered as an addition to the controversial discussion on the relationship between ASC and breast carcinoma cells. Further studies are needed to quantify the in vivo interaction of ASC and mammary carcinoma cells and to conclusively assess the impact of tamoxifen in reconstructive cases with fat grafting