Sleep deprivation modulates APOE and LDL receptor-related protein 1 through thyroid hormone T4 and impairs Aß clearance in hippocampus of rats.

Alzheimer's disease is the most common form of dementia. One of its pathological hallmarks is Aß accumulation, which is influenced by APOE genotype and expression, as well as by sleep homeostasis. However, conflicting mechanisms for APOE roles in Aß clearance have been reported, and the relationship between APOE and sleep also remains unclear. In this study, we aimed to investigate how hormonal alteration caused by sleep deprivation affects APOE and its receptors in rats, and to evaluate the role of different cell types in Aß clearance. Paradoxical sleep deprivation for 96 h increased Aß level in hippocampus with concomitant reduction of APOE and LRP1 at the time point within the resting period. Sleep deprivation also significantly reduced T4 levels in both active and resting times. To evaluate the effect of T4 variation, C6 glial cells and primary brain endothelial cells were treated with T4. High T4 level (300 ng/mL) increased APOE, but reduced LRP1 and LDL-R in C6 cells, while in primary endothelial cells, LDL-R levels were increased. Treatment of C6 cells with exogenous APOE reduced LRP1 and Aß uptake. These results suggest that T4 modulates LRP1 and LDL-R in both cell types, but in the opposite manner, thus, sleep deprivation might modify the ratio of the receptors in blood-brain barrier and glial cells by altering T4 levels. Considering that LRP1 and LDL-R are important for Aß clearance, sleep deprivation might also affect the degree of participation of glia in Aß clearance, and consequently, turnover of Aß in the brain.

Anesthesia can alter the levels of corticosterone and the phosphorylation of signaling molecules.

OBJECTIVE: Neuroscience research using laboratory animals has increased over the years for a number of reasons. Some of these studies require the use of anesthetics for surgical procedures. However, the use of anesthetics promotes several physiological changes that may interfere with experimental results. Although the anesthetics and methods of delivery used to vary, one of the most common is ketamine associated with another compound such as xylazine. We aimed to evaluate the effect of ketamine and xylazine (KX) on corticosterone levels and on the degree of phosphorylation of p44/42 (ERK1/2), Src kinases and calcium/calmodulin-dependent kinase II (CAMKII). We also compared the effects of KX on sleep deprivation, which is known to affect the hormonal profile including corticosterone. RESULTS: We found that the use of KX can increase corticosterone levels and alter the degree of phosphorylation of signaling proteins.

Histopathological changes and oxidative damage in type I and type II muscle fibers in rats undergoing paradoxical sleep deprivation.

BACKGROUND: previous studies have shown that muscle atrophy is observed after sleep deprivation (SD) protocols; however, the mechanisms responsible are not fully understood. Muscle trophism can be modulated by several factors, including energy balance (positive or negative), nutritional status, oxidative stress, the level of physical activity, and disuse. The metabolic differences that exist in different types of muscle fiber may also be the result of different adaptive responses. To better understand these mechanisms, we evaluated markers of oxidative damage and histopathological changes in different types of muscle fibers in sleep-deprived rats. METHODS: Twenty male Wistar EPM-1 rats were randomly allocated in two groups: a control group (CTL group; n = 10) and a sleep deprived group (SD group; n = 10). The SD group was submitted to continuous paradoxical SD for 96  h; the soleus (type I fibers) and plantar (type II fiber) muscles were analyzed for histopathological changes, trophism, lysosomal activity, and oxidative damage. Oxidative damage was assessed by lipid peroxidation and nuclear labeling of 8-OHdG. RESULTS: The data demonstrated that SD increased the nuclear labeling of 8-OHdG and induced histopathological changes in both muscles, being more evident in the soleus muscle. In the type I fibers there was signs of tissue degeneration, inflammatory infiltrate and tissue edema. Muscle atrophy was observed in both muscles. The concentration of malondialdehyde, and cathepsin L activity only increased in type I fibers after SD. CONCLUSION: These data indicate that the histopathological changes observed after 96 h of SD in the skeletal muscle occur by different processes, according to the type of muscle fiber, with muscles predominantly composed of type I fibers undergoing greater oxidative damage and catabolic activity, as evidenced by a larger increase in 8-OHdG labeling, lipid peroxidation, and lysosomal activity.

Expression of Tyrosine Hydroxylase is Negatively Regulated Via Prion Protein.

Cellular prion protein (PrP(C)) is a glycoprotein of the plasma membrane that plays pleiotropic functions by interacting with multiple signaling complexes at the cell surface. Recently, a number of studies have reported the involvement of PrP(C) in dopamine metabolism and signaling, including its interactions with tyrosine hydroxylase (TH) and dopamine receptors. However, the outcomes reported by independent studies are still debatable. Therefore in this study, we investigated the effects of PrP(C) on the TH expression during the differentiation of N2a cells with dibutyryl-cAMP, a well-known cAMP analog that activates TH transcription. Upon differentiation, TH was induced with concomitant reduction of PrP(C) at protein level, but not at mRNA level. shRNA-mediated PrP(C) reduction increased the basal level of TH at both mRNA and protein levels without dibutyryl-cAMP treatment. This phenotype was reversed by re-expression of PrP(C). PrP(C) knockdown also potentiated the effect of dibutyryl-cAMP on TH expression. Our findings suggest that PrP(C) has suppressive effects on TH expression. As a consequence, altered PrP(C) functions may affect the regulation of dopamine metabolism and related neurological disorders.