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Pregnenolone sulfate levels of PC-12 cells treated with Chol, AB 1–40 and “AB 1–40 + Chol”. PS levels of AB 1–40 and “AB 1–40 + Chol (1.2 mM)” treated cells were higher than the control, “AB 1–40 + Chol (9 mM)” treatment significantly increased PS level when compared with other groups. (Results are expressed as mM per 2 × 10⁶ PC 12 cells, data are given as mean ± SEM, Chol: Cholesterol, AB: Amyloid beta 1–40). (*p < 0.05 compared to control group). (**p < 0.05 compared to all groups)
Source publication
Increased amyloid beta (AB) peptide concentration is one of the initiating factors in the neurodegeneration process. It has been suggested that cholesterol induces the synthesis of AB peptide from amyloid precursor protein or facilitates the formation of amyloid plaque by lowering the aggregation threshold of the peptide. It is also shown that AB p...
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Background:
Late-onset Alzheimer's disease (AD) is highly heritable. The effect of many common genetic variants, single nucleotide polymorphisms (SNPs), confer risk. Variants are clustered in areas of biology, notably immunity and inflammation, cholesterol metabolism, endocytosis, and ubiquitination. Polygenic scores (PRS), which weight the sum of...
Citations
... The Aβ25-35 is the C-terminal peptide of Aβ1-42, and it is frequently preferred in vitro experimental setups for Alzheimer's disease (Calan et. al. 2016). Aβ25-35 stock solution was prepared in ultra-pure water and stored at -20 o C. In the Aβ25-35 groups, Aβ25-35 with a nal concentration of 20 µM was added to the six wells plates as described in the previous study. (Zhang et al. 2014). Because approximately 50% cell death was observed at 24 h and 20 µM dose. Non-treated differentiated ...
Purpose
To analyze the expressional changes in the PI3K/Akt/GSK-3β pathway and metalloprotease in the cellular AD model with the effect of antioxidant resveratrol.
Methods
We obtained neuron-like cells by a two-step method of neuronal differentiation by using a combination of retinoic acid (RA) and brain-derived factor (BDNF) exposure. Then, the application of the Aβ25–35 protein (10 µM) to the cell culture mimicked the environmental toxicity observed in Alzheimer's disease. Afterward, cell viability and apoptosis assays were performed to determine whether the resveratrol exerts a cytotoxic and apoptotic effect. Finally, we analyzed with Real-Time PCR, the expressional changes in genes in the cellular AD model with the effect of resveratrol.
Results
Apoptosis data findings were decreased by 1.5-fold and 2.5-fold respectively by differentiated + RES and RES when compared to control but no significant difference was observed between resveratrol and AD model groups. Real-time PCR analysis results revealed PI3K (3.38-fold), AKT (3.95-fold), and RELN (1.99-fold) expressions were significantly higher (p < 0.001), and also GSK-3β, TAU, ADAMTS-4, ADAMTS-5, and TIMP-3 gene expression levels were significantly downregulated (2.53-, 1.79-, 2.85-, 4.09-, and 6.62- fold, respectively) in the differentiated + Aβ + RES groups compared to the differentiated + Aβ group (p < 0.001).
Conclusion
Resveratrol has inhibited GSK-3β by activating the PI3K/Akt insulin pathway in a neurotoxic environment. In addition, TAU, RELN, metalloproteases, and their inhibitors associated with Alzheimer's pathology have been regulated supporting the neuroprotective effect of resveratrol.
... have been evaluated together (Ali et al., 2021;Zeng et al., 2022). Since the SH-SY5Y cell line is thought to mimic neurons in physiological and pathological conditions, it is frequently used in in vitro models for AD and in neurodegeneration mechanism studies (Calan et al., 2016;Gao et al., 2017). The bEnd.3 cell line is also frequently used in AD cell culture studies because of its paracellular barrier properties (Watanabe et al., 2013). ...
Abstract Donepezil-HCl is a member of the acetylcholinesterase inhibitors that is indicated for the symptomatic treatment of Alzheimer’s disease (AD) and has many side effects. In this study, to reduce the side effects of Donepezil-HCl and increase the penetration of the drug through the blood-brain barrier, we aimed to design a solid lipid nanoparticle (SLN) formulation. The effects of the different formulation parameters, such as homogenization speed, sonication time, lipid and drug concentration, surfactant type and concentration, and volume of the aqueous phase, were assessed for optimization. The particle size and PDI increased with increasing lipid concentration but decreased with increasing amounts of surfactant (Tween 80) and co-surfactant (lecithin). When the homogenization rate and sonication time increased, the particle size decreased and the encapsulation efficiency increased. The optimized formulation exhibited particle size, PDI, encapsulation efficiency, and zeta potential of 87.2±0.11 nm; 0.22±0.02; 93.84±0.01 %; -17.0±0.12 mV respectively. The in vitro release investigation revealed that approximately 70% of Donepezil-HCl was cumulatively released after 24 hours. TEM analysis proved that spherical and smooth particles were obtained and formulations had no toxic effect on cells. The final optimized formulation could be a candidate for Donepezil-HCl application in Alzheimer’s treatment with reduced side effects and doses for patients.
... Sex hormones can influence growth, synaptogenesis, dendritic branching, and myelination (Calan et al., 2016), and other important mechanisms of neuroplasticity (Calan et al., 2016). Sex hormones are released into various tissues and the brain via the bloodstream. ...
... Sex hormones can influence growth, synaptogenesis, dendritic branching, and myelination (Calan et al., 2016), and other important mechanisms of neuroplasticity (Calan et al., 2016). Sex hormones are released into various tissues and the brain via the bloodstream. ...
Introduction
Alzheimer’s disease (AD) is the most common form of dementia worldwide. This study investigated the effects of lipopolysaccharide on neurosteroidogenesis and its relationship to growth and differentiation using SH-SY5Y cells.
Methods
In this study, we used the MTT assay to assess the impact of LPS on SH-SY5Y cell viability. We also evaluated apoptotic effects using FITC Annexin V staining to detect phosphatidylserine in the cell membrane. To identify gene expression related to human neurogenesis, we utilized the RT² Profiler TM PCR array human neurogenesis PAHS-404Z.
Results
Our study found that LPS had an IC50 level of 0.25 μg/mL on the SH-SY5Y cell line after 48 h. We observed Aβ deposition in SH-SY5Y cells treated with LPS, and a decrease in DHT and DHP levels in the cells. Our analysis showed that the total rate of apoptosis varied with LPS dilution: 4.6% at 0.1 μg/mL, 10.5% at 10 μg/mL, and 44.1% at 50 μg/mL. We also observed an increase in the expression of several genes involved in human neurogenesis, including ASCL1, BCL2, BDNF, CDK5R1, CDK5RAP2, CREB1, DRD2, HES1, HEYL, NOTCH1, STAT3, and TGFB1, after treatment with LPS at 10 μg/mL and 50 μg/mL. LPS at 50 μg/mL increased the expression of FLNA and NEUROG2, as well as the other genes mentioned.
Conclusion
Our study showed that LPS treatment altered the expression of human neurogenesis genes and decreased DHT and DHP levels in SH-SY5Y cells. These findings suggest that targeting LPS, DHT, and DHP could be potential therapeutic strategies to treat AD or improve its symptoms.
... Schwann cells were found to be a key producer of steroid hormones in the peripheral nervous system, and P5 synthesis by P450scc was a crucial regulatory step during myelination. 10 Furthermore, P5 reduced subsequent histological changes in vivo after spinal cord damage, protected neural tissue from secondary lesions, and improved motor function recovery. P5 may affect the neuronal cytoskeleton dynamics via binding to microtubule-associated protein 2. This neuroprotective effect could be due to P5's direct action on the spinal cord neurons (MAP2). ...
Neurosteroids are apparent to be connected in the cerebral ischemic injury for their potential neuroprotective effects. We previously demonstrated that progesterone induces neuroprotection via the mitochondrial cascade in the cerebral ischemic stroke of rodents. Here, we sought to investigate whether or not pregnenolone, a different neurosteroid, can protect the ischemic injury in the transient middle cerebral artery occlusion (tMCAO) rodent model. Male Wistar rats were chosen for surgery for inducing stroke using the tMCAO method. Pregnenolone (2 mg/kg b.w.) at 1 h postsurgery was administered. The neurobehavioral tests and (TTC staining) 2, 3, 5-triphenyl tetrazolium chloride staining were performed after 24 h of the surgery. The mitochondrial membrane potential and reactive oxygen species (ROS) were measured using flow cytometry. Oxygraph was used to examine mitochondrial bioenergetics. The spectrum of neurobehavioral tests and 2, 3, 5-triphenyltetrazolium chloride staining showed that pregnenolone enhanced neurological recovery. Pregnenolone therapy after a stroke lowered mitochondrial ROS following ischemia. Our data demonstrated that pregnenolone was not able to inhibit mitochondrial permeability transition pores. There was no effect on mitochondrial bioenergetics such as oxygen consumption and respiratory coupling. Overall, the findings demonstrated that pregnenolone reduced the neurological impairments via reducing mitochondria ROS but not through the inhibition of the mitochondria permeability transition pore (mtPTP).
... These reduced PREGS and DHEAS levels suggested that the 3β-HST enzyme involved in their biosynthesis was reduced. However, Calan et al. 2016 [40] showed that toxic doses of Aβ significantly increased PREGS cellular levels in a time-dependent manner in SH-SY5Y cultured cells as compared to control cells ( Figure 2A). This enhanced steroid production was interpreted as a result of self-defense probably to overcome harmful effects of Aβ. ...
... In the studies by Marx et al. 2006 andNaylor et al. 2010 [41,42], high DHEA and PREG concentrations were observed in the prefrontal and temporal cortices of AD patients and tended to be positively correlated with Braak and Braak stage [41]. Similarly, in SH-SY5Y neuronal cells, treatment with Aβ peptides (Aβ 25-35 , Aβ 1-40 or Aβ 1-42 ) at toxic doses significantly enhanced PREG levels [40] ( Figure 2B). PREG levels were higher in the group treated with Aβ 25-35 than the two others and proportionate to cell cholesterol content. ...
Alzheimer’s disease (AD) is a multifactorial age-related neurodegenerative disease that today has no effective treatment to prevent or slow its progression. Neuroactive steroids, including neurosteroids and sex steroids, have attracted attention as potential suitable candidates to alleviate AD pathology. Accumulating evidence shows that they exhibit pleiotropic neuroprotective properties that are relevant for AD. This review focuses on the relationship between selected neuroactive steroids and the main aspects of AD disease, pointing out contributions and gaps with reference to sex differences. We take into account the regulation of brain steroid concentrations associated with human AD pathology. Consideration is given to preclinical studies in AD models providing current knowledge on the neuroprotection offered by neuroactive (neuro)steroids on major AD pathogenic factors, such as amyloid-β (Aβ) and tau pathology, mitochondrial impairment, neuroinflammation, neurogenesis and memory loss. Stimulating endogenous steroid production opens a new steroid-based strategy to potentially overcome AD pathology. This article is part of a Special Issue entitled Steroids and the Nervous System.
... A prior study demonstrated that cholesterol interacts with Aβ peptides, promotes the insertion of Aβ, and affects subsequent cytotoxicity. 16,17 It interacts with Aβ and facilitate Aβ aggregation on the membrane. 18 They also reported that increased cholesterol facilitates Aβ insertion. ...
The misfolding of amyloid beta (Aβ) is one of the predominant hallmarks in the pathology of Alzheimer’s disease (AD). In this study, we showed that the formation of Aβ ion channel on the membrane depended on cholesterol concentration. From a mechanical aspect, we found that cholesterol levels affected the stability and assembly of lipid bilayers. Measurements on planar lipid bilayers indicated that a small amount of cholesterol interacted with Aβ proteins and promoted the insertion process. Conversely, high cholesterol integrated the lipid bilayer and exerted an opposite effect on Aβ insertion. Aβ ion channel was then detected by graphene-based field-effect transistors. Results demonstrated that Aβ ion channel promoted Ca2+ flux in the presence of 15% cholesterol but prevent Ca2+ flux in high cholesterol. Thus, cholesterol had a complex impact on Aβ ion channel that can be described as two different effects. First, a small amount of cholesterol interacted with Aβ and facilitated Aβ ion-channel formation in the membrane. Second, a large amount of cholesterol did not induce ion flux in the membrane, which can be explained by the cholesterol damage to the regular distribution of the lipid bilayer. Overall, this study suggested a possible approach to consider cholesterol levels for the treatment of AD patients.
... The results of the supplementary experiments showed that both Aβ 1-42 and Aβ 1-40 significantly induced decrease in cell viability, and there are no significant differences in cell viability between Aβ 1-40 and Aβ 1-42 treatment (Supporting Information Figure S1A), which is consistent with the previous study. [36] In addition, EGCG treatment also significantly inhibited the expression levels of GRP78, CHOP and cleaved-caspase12 in both Aβ 1-42 -and Aβ 1-40 -induced Figure 5. Effect of EGCG on cleaved-caspase3 expression in the cerebral cortex of APP/PS1 mice. ...
Scope:
We investigated the role of endoplasmic reticulum (ER) stress in the protective effects of EGCG against the neuronal apoptosis in Aβ1-42-induced SH-SY5Y cells and APP/PS1 transgenic mice.
Methods and results:
Cell viability (CCK8 assay), flow cytometry, Hoechst 33258 staining, immunohistochemistry, Transmission Electron Microscopy (TEM), western blotting were used. EGCG prevented Aβ1-42-induced toxicity in SH-SY5Y cells, increased cell viability and decreased apoptosis in a dose-dependent manner. In a subsequent mechanism study, we found that this effect contributed to the down-regulation of GRP78, CHOP, cleaved-caspase-12 and -3. Moreover, EGCG also reduced the cytotoxicity induced by tunicamycin (TM) and thapsigargin (TG), two ER stress activators. In consistent with in vitro study, EGCG inhibited neuronal apoptosis in the cortex of APP/PS1 transgenic mice, with the mitigation of ER abnormal ultrastructural swelling and the downregulation of ER stress associated-proteins.
Conclusion:
These results indicated that EGCG attenuated the neurotoxicity in AD via a novel mechanism that involved inhibition of ER stress-associated neuronal apoptosis in vitro and in vivo, suggesting the tremendous potential of EGCG for use in a nutritional preventive strategy against AD. This article is protected by copyright. All rights reserved.
... Progesterone is another key reproductive hormone whose levels escalate throughout gestation, although it exerts no significant effect on lipoprotein metabolism. Studies in premenopausal women administered with the progesterone-only pill have shown marginal reductions in the levels of circulating total cholesterol and triglycerides [45] . However, it has been suggested that the administration of progesterone derivatives is able to blunt the changes in serum lipid profiles due to estrogen [46] . ...
Background:
Pregnancy is a dynamic state involving multiple adaptations that are necessary in order to ensure a continuous supply of essential metabolites to support the growth and the development of the fetus.
Objectives:
This review article is aimed to discuss important adaptations in metabolism that take place during non-complicated pregnancy.
Materials and methods:
We searched the electronic database PubMed for pre-clinical as well as clinical controlled trials reporting the importance of metabolic adaptations during a non-complicated pregnancy. The preferred language was English and the most recent reports were selected to get an updated review.
Results:
It was observed clearly in the searched literature that metabolic adaptations are a crucial part of pregnancy, as they provide the mother with sufficient energy stores to meet the demands of pregnancy. These adaptions also help in preparing the mother for lactation and also help in providing proper environment for the proper growth of fetus in the womb. Moreover, multiple biomolecules including glucose, fatty acids, ketone bodies, hormones collectively contribute toward these metabolic adaptations.
Conclusions:
This review article concludes that metabolic adaptations are crucial for proper fetus development.
Magnetic levitation (MagLev) is a powerful and versatile technique that can sort objects based on their density differences. This paper reports the sorting of SH-SY5Y cells for neuronal differentiation by the MagLev technique. Herein, SH-SY5Y cells were differentiated with retinoic acid (RA) and brain-derived neurotrophic factor (BDNF). Neuronal differentiation was confirmed by neurite extension measurement and the immunostaining assay. Neurites reached the maximum length on day 9 after sequential treatment with RA-BDNF. Neuronal marker expression of un-/differentiated cells was investigated by β-III tubulin and neuronal nuclei (NeuN) and differentiated cells exhibited a higher fluorescence intensity compared to un-/differentiated cells. MagLev results revealed that the density of differentiated SH-SY5Y cells gradually increased from 1.04 to 1.06 g/mL, while it remained stable at 1.05 g/mL for un-/differentiated cells. These findings signified that cell density would be a potent indicator of neuronal differentiation. Overall, it was shown that MagLev methodology can provide rapid, label-free, and easy sorting to analyze the differentiation of cells at a single-cell level.
