Alzheimer's Disease Indicator-1 Research Articles

DHCR24 overexpression modulates microglia polarization and inflammatory response via Akt/GSK3β signaling in Aβ25–35 treated BV-2 cells

Microglial phenotypic polarization, divided into pro-inflammatory “M1” phenotype and anti-inflammatory “M2” phenotype, played a crucial role in the pathogenesis of Alzheimer's disease (AD). Facilitating microglial polarization from M1 to M2 phenotype was shown to alleviate AD-associate pathologic damage, and modulator of the microglial phenotype has become a promising therapeutic approach for the treatment of AD. Previous little evidence showed that DHCR24 (3-β-hydroxysteroid-Δ-24-reductase), also known as seladin-1 (selective Alzheimer's disease indicator-1), exerted potential anti-inflammatory property, however, the link between DHCR24 and microglial polarization has never been reported. Thus, the role of DHCR24 in microglial polarization in amyloid-beta 25–35 (Aβ25–35) treated BV-2 cells was evaluated in this study. Our results demonstrated that Aβ25–35 aggravated inflammatory response and facilitated the transition of microglia phenotype from M2 to M1 in BV-2 cells, by upregulating M1 marker (i-NOS, IL-1β and TNF-α) and downregulating M2 marker (arginase-1, IL-4 and TGF-β). DHCR24 overexpression by lentivirus transfection could significantly reverse these effects, meanwhile, activated Akt/GSK3β signaling pathway via increasing the protein expression of P-Akt and P-GSK3β. Furthermore, when co-treated with Akt inhibitor MK2206, the effect of DHCR24 was obviously reversed. The study exhibited the neuroprotective function of DHCR24 in AD-related inflammatory injury and provided a novel therapeutic target for AD in the future.

Serum seladin-1 levels in diabetes mellitus and Alzheimer's disease patients.

Diabetes mellitus (DM) has been shown to increase the risk of Alzheimer's disease (AD). Downregulation of selective Alzheimer's disease indicator-1 (seladin-1) occurs in the cerebral regions affected by AD. However, inconsistent results have been reported for the relationship between seladin-1 levels and AD. The effect of DM on serum seladin-1 levels in AD is unknown. The present study is aimed to investigate serum seladin-1 levels in diabetic and non-diabetic patients with AD. Forty-six patients with AD and 25 healthy volunteers over 65years of age were included in this study. The patients were divided into three groups-those with AD only, those with DM and AD, and control groups. Demographic characteristics and serum seladin-1 levels were compared among the groups. There was no statistically significant difference in seladin-1 levels in the AD only group compared to the control group (p = 0.376). However, seladin-1 levels were significantly lower in the DM and AD group compared to the AD only and control groups (p = 0.002, p = 0.001; respectively). Negative correlations were present between seladin-1 and fasting glucose, postprandial glucose, HbA1c, and insulin (p < 0.05; all). Decreased serum seladin-1 values in the presence of DM and inverse correlations with diabetic parameters in patients with AD, together with a non-significant difference from the control group, suggests that seladin-1 may be altered only in the presence of DM in patients with AD. Lower serum seladin-1 levels may also play a role in the pathogenesis of AD in patients with DM.

Upregulation of seladin-1 and nestin expression in bone marrow mesenchymal stem cell transplantation via the ERK1/2 and PI3K/Akt signaling pathways in an Alzheimer's disease model.

The aim of the present study was to determine the roles of bone marrow mesenchymal stem cell (BM-MSC) transplantation in a model of Alzheimer's disease (AD) and determine the underlying mechanism. The expression of selective Alzheimer's disease indicator-1 (Seladin-1) and nestin was detected using reverse transcription-quantitative polymerase chain reaction and western blot analysis. The phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (ERK)1/2 inhibitors, LY294002 and PD98059, were employed to evaluate the molecular mechanism. The results indicated that the mRNA and protein expression of Seladin-1 and nestin was lower in the AD group when compared with the control group. BM-MSC transplantation reversed this decrease in expression, potentially by increasing the protein expression of phosphorylated (p)-protein kinase B (Akt) and p-ERK1/2. In addition, LY294002 (the PI3K inhibitor) and/or PD98059 (the ERK1/2 inhibitor) blocked the enhancement of BM-MSC transplantation on the expression of Seladin-1 and nestin in the hippocampus. These results indicated that BM-MSC transplantation enhanced Seladin-1 and nestin expression potentially via a mechanism associated with the activation of the PI3K/Akt and ERK1/2 signaling pathways. The present study offers preliminary evidence that treatment with BM-MSCs may represent a potential therapeutic approach against brain lesions in AD.

Neuroprotective effects of estrogens: the role of cholesterol.

Experimental and clinical evidence suggests that estrogens have protective effects in the brain. Nevertheless, their potential role against neurodegenerative diseases, in particular Alzheimer's disease (AD), is still a matter of debate. The identification of the seladin-1 gene (for SELective Alzheimer's Disease INdicator-1), which appeared to be significantly less expressed in brain region affected in AD, opened a new scenario in the field of neuroprotective mechanisms. Seladin-1 was found to have neuroprotective properties through its anti-apoptotic activity. In addition, it was subsequently demonstrated that seladin-1 also has enzymatic activity, because it catalyzes the conversion of desmosterol into cholesterol. Several studies have shown that an appropriate amount of membrane cholesterol plays a pivotal role to protect nerve cells against β-amyloid toxicity in AD and to counteract the synthesis of β-amyloid. We demonstrated that the expression of seladin-1, as well as the synthesis of cell cholesterol, is stimulated by estrogens in human neuronal precursor cells. Cholesterol enriched cells became more resistant against oxidative stress and β-amyloid toxicity. We thus hypothesized that seladin-1 might be a mediator of the neuroprotective effects of estrogens. Indeed, in cells in which seladin-1 gene expression had been silenced by siRNA the protective effects of estrogens were lost. This finding indicates that seladin-1 is a crucial mediator of the neuroprotective effects of these hormones, at least in our cell model. In summary, these results establish a new link between estrogens and cholesterol, which is represented by the neuroprotective factor seladin-1.

Altered expression of 3-betahydroxysterol delta-24-reductase/selective Alzheimer's disease indicator-1 gene in Huntington's disease models.

3-betahydroxysterol delta-24-reductase (DHCR24), also called selective Alzheimer's disease indicator-1, is a crucial enzyme in cholesterol biosynthesis with neuroprotective properties that is downregulated in brain areas affected by Alzheimer's disease. In the present study, we investigated modifications of DHCR24 expression in models of Huntington's disease (HD), a neurodegenerative disorder caused by a polyglutamine expansion in huntingtin (Htt) protein that induces degeneration of cerebral cortex and striatum as well as lateral hypothalamic abnormality. Basal expression of DHCR24 and its modulation after oxidative stress were evaluated in rat striatal precursors cells (ST14A) transfected with wild-type (Htt) or mutant Htt (mHtt) and in brain tissue of an HD mouse model (R6/2). The results showed that DHCR24 transcript levels were decreased in ST14A cells expressing mHtt and in the brain of symptomatic R6/2 mice, but were significantly increased in ST14A cells overexpressing wild-type Htt. In addition, we demonstrated that, in the striatal precursors, the decrease of DHCR24 expression in response to oxidative stress was modified according to the presence of Htt or of its mutant form. Preliminary results indicated a modification of DHCR24 expression in post-mortem brain samples of HD patients. In conclusion, these results support the hypothesis of a possible role of DHCR24 in HD.

Is Seladin-1 Really a Selective Alzheimer's Disease Indicator?

Selective Alzheimer's Disease Indicator-1 (Seladin-1) was originally identified by its down-regulation in the brains of Alzheimer's disease (AD) patients. Here, we re-examine existing data and present new gene expression data that refutes its role as a selective AD indicator. Furthermore, we caution against the use of the name "Seladin-1" and instead recommend adoption of the approved nomenclature, 3β-hydroxysterol Δ24-reductase (or DHCR24), which describes its catalytic function in cholesterol synthesis. Further work is required to determine what link, if any, exists between DHCR24 and AD.

Membrane cholesterol as a mediator of the neuroprotective effects of estrogens

Alzheimer's disease (AD), the most common neurodegenerative disease associated with aging, is still an incurable condition. Although in vitro evidence strongly indicates that estrogens exert neurotrophic and neuroprotective effects, the role of this class of hormones in the treatment of AD is still a debated issue. In 2000 a new gene, named seladin-1 (for SELective Alzheimer's Disease INdicator-1), was identified and found to be down regulated in vulnerable brain regions in AD. Seladin-1 was considered a novel neuroprotective factor, because of its anti-apoptotic activity. Subsequently, it was demonstrated that seladin-1 has also enzymatic activity [3-β-hydroxysterol delta-24-reductase, (DHCR24)], which catalyzes the synthesis of cholesterol from desmosterol. The amount of membrane cholesterol may play an important role both in protecting neuronal cells against toxic insults and in inhibiting the production of β-amyloid. We demonstrated that seladin-1 overexpression increases the amount of membrane cholesterol and induces resistance against β-amyloid aggregates in neuroblastoma cells, whereas a specific inhibitor of DHCR24 increased cell vulnerability. We also hypothesized that seladin-1 might be a mediator of the neuroprotective effects of estrogens. We first demonstrated that, in human fetal neuroepithelial cells (FNC), 17β-estradiol, raloxifene, and tamoxifen exert protective effects against β-amyloid toxicity and oxidative stress. In addition, these molecules significantly increased the expression of seladin-1 and the amount of cell cholesterol. Then, we showed that, upon seladin-1 silencing, the protective effects of estrogens were abolished, thus indicating this factor as a fundamental mediator of estrogen-mediated neuroprotection, at least in FNC cells. Furthermore, we detected the presence of functionally active half-palindromic estrogen responsive elements upstream the coding region of the seladin-1 gene. Overall, our results indicate that seladin-1 may be viewed as a multi-faceted protein, which conjugates both the neuroprotective properties of estrogens and the important functions of cholesterol in maintaining brain homeostasis. This article is part of a Special Issue entitled: Neuroactive Steroids: Focus on Human Brain.

Estrogen receptor-mediated neuroprotection: The role of the Alzheimer&amp;rsquo;s disease-related gene seladin-1

Experimental evidence supports a protective role of estrogen in the brain. According to the fact that Alzheimer's disease (AD) is more common in postmenopausal women, estrogen treatment has been proposed. However, there is no general consensus on the beneficial effect of estrogen or selective estrogen receptor modulators in preventing or treating AD. It has to be said that several factors may markedly affect the efficacy of the treatment. A few years ago, the seladin-1 gene (for selective Alzheimer's disease indicator-1) has been isolated and found to be down-regulated in brain regions affected by AD. Seladin-1 has been found to be identical to the gene encoding the enzyme 3-beta-hydroxysterol delta-24-reductase, involved in the cholesterol biosynthetic pathway, which confers protection against beta-amyloid-mediated toxicity and from oxidative stress, and is an effective inhibitor of caspase-3 activity, a key mediator of apoptosis. Interestingly, we found earlier that the expression of this gene is up-regulated by estrogen. Furthermore, our very recent data support the hypothesis that seladin-1 is a mediator of the neuroprotective effects of estrogen. This review will summarize the current knowledge regarding the neuroprotective effects of seladin-1 and the relationship between this protein and estrogen.

Thyroid hormones promote cell differentiation and up-regulate the expression of the seladin-1 gene in in vitro models of human neuronal precursors

Thyroid hormones (TH) play an important role in the development of human brain, by regulating the expression of specific genes. Selective Alzheimer's disease indicator-1 (seladin-1) is a recently discovered gene with neuroprotective properties, which has been found to be down-regulated in brain regions affected by Alzheimer's disease. Seladin-1 has anti-apoptotic properties mainly due to the inhibition of the activation of caspase 3. The aim of this study was to determine whether seladin-1 may be regarded as a new mediator of the effects of TH in the developing brain. In order to demonstrate this hypothesis, the effects of TH both on cell differentiation and on the expression of seladin-1 were assessed in two different cell models, i.e. fetal human neuroepithelial cells (FNC) and human mesenchymal stem cells (hMSC), which can be differentiated into neurons. 3,3',5-Triiodothyronine (T3) determined different biological responses (inhibition of cell adhesion, induction of migration, and increase in the expression of the neuronal marker neurofilament-M and Na+ and Ca2+ channel functionality) in both FNC and hMSC, which express TH receptors. Then, we showed that TH significantly increase the expression levels of seladin-1, and that T3 effectively prevents camptothecin-induced apoptosis. However, in hMSC-derived neurons the expression of seladin-1 was not affected by TH. Our results demonstrated for the first time that seladin-1 is a novel TH-regulated gene in neuronal precursors. In view of its anti-apoptotic activity, it might be hypothesized that one of the functions of the increased seladin-1 levels in the developing brain may be to protect neuronal precursor cells from death.

Neuronal differentiation of human mesenchymal stem cells: Changes in the expression of the Alzheimer's disease-related gene seladin-1

Seladin-1 (SELective Alzheimer's Disease INdicator-1) is an anti-apoptotic gene, which is down-regulated in brain regions affected by Alzheimer's disease (AD). In addition, seladin-1 catalyzes the conversion of desmosterol into cholesterol. Disruption of cholesterol homeostasis in neurons may increase cell susceptibility to toxic agents. Because the hippocampus and the subventricular zone, which are affected in AD, are the unique regions containing stem cells with neurogenic potential in the adult brain, it might be hypothesized that this multipotent cell compartment is the predominant source of seladin-1 in normal brain. In the present study, we isolated and characterized human mesenchymal stem cells (hMSC) as a model of cells with the ability to differentiate into neurons. hMSC were then differentiated toward a neuronal phenotype (hMSC-n). These cells were thoroughly characterized and proved to be neurons, as assessed by molecular and electrophysiological evaluation. Seladin-1 expression was determined and found to be significantly reduced in hMSC-n compared to undifferentiated cells. Accordingly, the total content of cholesterol was decreased after differentiation. These original results demonstrate for the first time that seladin-1 is abundantly expressed by stem cells and appear to suggest that reduced expression in AD might be due to an altered pool of multipotent cells.

Expression of the novel adrenocorticotropin-responsive gene selective Alzheimer's disease indicator-1 in the normal adrenal cortex and in adrenocortical adenomas and carcinomas.

Selective Alzheimer's disease indicator-1 (seladin-1) is a novel gene with antiapoptotic activity that is down-regulated in vulnerable brain regions in Alzheimer's disease. This gene encodes 3-beta-hydroxysterol Delta-24-reductase (DHCR24), which converts desmosterol into cholesterol. In the adrenal cortex, increased expression of seladin-1/DHCR24, which appears to be modulated by ACTH, has been recently reported in cortisol-secreting adenomas, compared with the adjacent atrophic tissue. In our study, we measured the expression level of seladin-1/DHCR24 in cortisol- (n = 18) and aldosterone-secreting (n = 16) adrenocortical adenomas, in carcinomas (n = 17), and in normal adrenal glands (n = 8) by quantitative real-time RT-PCR. The amount of seladin-1/DHCR24 mRNA was significantly reduced in carcinomas (total RNA, 2.5 +/- 0.8 pg/ micro g) compared with the other groups (P < 0.01). Western blot analysis confirmed the mRNA results. Similarly, in adrenal malignancies, significantly reduced levels of expression of the ACTH receptor gene were found. In the adrenal cancer cell line H295R and in primary cultures from adrenocortical cells, ACTH (1 nM) and forskolin (10 micro M) effectively increased seladin-1/DHCR24 expression, confirming that seladin-1/DHCR24 is modulated by the ACTH/cAMP-driven pathway. In summary, this is the first demonstration that seladin-1/DHCR24 expression is reduced in adrenal cancer, suggesting that it might be viewed as a new potential marker of adrenal malignancies.