Tocotrienol Affects Oxidative Stress, Cholesterol Homeostasis and the Amyloidogenic Pathway in Neuroblastoma Cells: Consequences for Alzheimer’s Disease

Abstract

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.

Potential Role of Tocotrienols on Non-Communicable Diseases: A Review of Current Evidence

“…Saito and co-authors reported that αTF and αT3 attenuated cell death induced by glutamate using primary cortical neurons isolated from cerebral cortex of Sprague-Dawley rats fetuses [276]. Another in vitro study using human neuroblastoma (SH-SY5Y) cells found that αTF and αT3 decreased cholesterol and ROS like hypochlorite (-OCl) and free hydroxyl radical (OH) as vitamin E had been proposed to have cholesterol-lowering and antioxidant effects [277]. However, the study also revealed enhanced Aβ production and reduced Aβ degradation in αT3-treated cells [277].…”

“…Another in vitro study using human neuroblastoma (SH-SY5Y) cells found that αTF and αT3 decreased cholesterol and ROS like hypochlorite (-OCl) and free hydroxyl radical (OH) as vitamin E had been proposed to have cholesterol-lowering and antioxidant effects [277]. However, the study also revealed enhanced Aβ production and reduced Aβ degradation in αT3-treated cells [277]. This side effect of T3 should be considered when initiating treatment in Alzheimer's disease subjects.…”

Biological Redox Impact of Tocopherol Isomers Is Mediated by Fast Cytosolic Calcium Increases in Living Caco-2 Cells

“…In other cellular models, such tocopherol as tocotrienol isomers has been studied regarding its capacity to protect cells from an oxidative challenge. For instance, 24 h preincubation with α-tocopherol or α-tocotrienol showed no differences in avoiding ROS generation in SH-SH5Y cells subjected to 1 µM H 2 O 2 for 40 min [26]. In cerebellar granular cells, on the other hand, 5 µM α-, γ-tocotrienol showed axonal and dendritic protection from structural damage induced by 0.5 µM H 2 O 2 (24 h) with some differences in the level of lipid peroxidation induced by H 2 O 2 .…”

Tocotrienols and Oxidative Stress in Oocytes and Developing Embryos

“…However, recent notable discoveries concerning TCT in over 900 published research articles in PubMed have established that this micronutrient, found abundantly in palm oil and barley, provides some health benefits not offered by TCP. Remarkably, TCT isomers have been shown to have more profound anti-oxidative, cholesterol lowering and anti-cancer effects than TCP [3][4][5]. Consequently, more investigators are now beginning to examine the benefits of TCT.…”