BACE1 Gene Expression Research Articles

The β-Secretase 1 Enzyme as a Novel Therapeutic Target for Prostate Cancer.

Recent studies have demonstrated the association of APP and Aβ with cancer, suggesting that BACE1 may play an important role in carcinogenesis. In the present study, we assessed BACE1's usefulness as a therapeutic target in prostate cancer (PCa). BACE1 expression was observed in human PCa tissue samples, patient-derived xenografts (PDX), human PCa xenograft tissue in nude mice, and transgenic adenocarcinoma of the mouse prostate (TRAMP) tissues by immunohistochemistry (IHC) analysis. Additionally, the downstream product of BACE1 activity, i.e., Aβ1-42 expression, was also observed in these PCa tissues by IHC as well as by PET imaging in TRAMP mice. Furthermore, BACE1 gene expression and activity was confirmed in several established PCa cell lines (LNCaP, C4-2B-enzalutamide sensitive [S], C4-2B-enzalutamide resistant [R], 22Rv1-S, 22Rv1-R, PC3, DU145, and TRAMP-C1) by real-time PCR and fluorometric assay, respectively. Treatment with a pharmacological inhibitor of BACE1 (MK-8931) strongly reduced the proliferation of PCa cells in in vitro and in vivo models, analyzed by multiple assays (MTT, clonogenic, and trypan blue exclusion assays and IHC). Cell cycle analyses revealed an increase in the sub-G1 population and a significant modulation in other cell cycle stages (G1/S/G2/M) following MK-8931 treatment. Most importantly, in vivo administration of MK-8931 intraperitoneal (30 mg/kg) strongly inhibited TRAMP-C1 allograft growth in immunocompetent C57BL/6 mice (approximately 81% decrease, p = 0.019). Furthermore, analysis of tumor tissue using the prostate cancer-specific pathway array revealed the alteration of several genes involved in PCa growth and progression including Forkhead O1 (FOXO1). All together, these findings suggest BACE1 as a novel therapeutic target in advanced PCa.

Anti‐amyloidogenic effect of BACE1 expression lowering compound identified using high‐throughput gene promoter assay

AbstractBackgroundAccumulation of Aβ in a brain is one of the pathological hallmarks of Alzheimer’s disease (AD). Aβ is generated through sequential cleavage of amyloid precursor protein (APP) by β‐secretase (BACE1) and γ‐secretase complex. BACE1 is one of the crucial targets for AD given that BACE1 expression is significantly upregulated in AD patients compared with non‐AD. However, direct and complete inhibition of BACE1 activity can cause unpredictable or unintended effects because of numerous physiological substrates of BACE1.MethodWe screened small compounds, including drugs approved by the U.S. Food and Drug Administration to identify medicines that reduce promoter activity of BACE1. TG reduced the levels of BACE1 protein and mRNA in APP‐SH‐SY5Y cells. In order to confirm the effect of TG regulating the expression BACE1, we constructed the RFP (BACE1 expression indicator) ‐GFP (cell body) U2OS cell line and compared the TG and analogs. After administration of TG,we carried out Morris Water Maze(MWM) test in APP/PS1 AD model mice. We did immunofluorescence assay in each group of mouse brains. We conducted an ELISA assay to determine quantitative changes in Aβ accumulation.ResultWe have found a new candidate drug that reduces promoter activity, mRNA, and protein levels of BACE1 in neuronal cells. We have confirmed that the drug decreases the BACE1 gene expression, prevents accumulation of Aβ, and improves cognitive function in APP/PS1 transgenic mice.ConclusionThe ability of this compound reverses a wide range of deficits suggests that BACE1 expression reducing agents may have therapeutic utility in the treatment of AD

Diurnal Characteristics of the Orexin System Genes and Its Effects on Pathology at Early Stage in 3xTg-AD Mice.

Orexin and its receptors are closely related to the pathogenesis of Alzheimer's disease (AD). Although the expression of orexin system genes under physiological condition has circadian rhythm, the diurnal characteristics of orexin system genes, and its potential role in the pathogenesis in AD are unknown. In the present study, we hope to elucidate the diurnal characteristics of orexin system genes at the early stage of AD, and to investigate its potential role in the development of AD neuropathology. We firstly detected the mRNA levels of orexin system genes, AD risk genes and core clock genes (CCGs) in hypothalamus and hippocampus in 6-month-old male 3xTg-AD mice and C57BL/6J (wild type, WT) control mice, then analyzed diurnal expression profiles of all genes using JTK_CYCLE algorithm, and did the correlation analysis between expression of orexin system genes and AD risk genes or CCGs. In addition, the expression of β-amyloid protein (Aβ) and phosphorylated tau (p-tau) protein were measured. The results showed that the diurnal mRNA expression profiles of PPO, OX1R, OX2R, Bace2, Bmal1, Per1, Per2 and Cry1 in the hypothalamus, and gene expression of OX1R, OX2R, Bace1, Bmal1, Per1 and Cry2 in the hippocampus in 3xTg-AD mice were different from that in WT mice. Furthermore, there is positive correlation between orexin system genes and AD risk genes or CCGs in the brain in 3xTg-AD mice. In addition, the expression of Aβ and p-tau in hippocampus in 3xTg-AD mice were significantly increased, and the expression of p-tau is higher in night than in day. These results indicate that the abnormal expression profiles of orexin system genes and its interaction with AD risk genes or CCGs might exert important role in the pathogenesis of AD, which will increase the expression of Aβ and p-tau, and accelerate the development of AD.

HOW INTERPLAY BETWEEN INFLAMMASOME AND MIRNA IS ASSOCIATED WITH ALZHEIMER’S DISEASE

Abstract The results of recent analyses showed that neuroinflammation—a key contributor to Alzheimer’s disease (AD)—is activated by protein complexes known as inflammasomes. The NLRP3 inflammasome protein complex is mostly studied in the central nervous system; it includes a protein encoded by the NLRP3 gene. Connections between inflammasomes, neuroinflammation, and AD may be regulated by small non-coding RNAs called microRNAs. These molecules have multiple ways to influence AD. For example, microRNA miR-107 may influence AD through regulation of the BACE1 gene expression involved in Aβ production. It remains unclear whether interplay of miR-107 and NRLP3 is associated with AD and whether mechanisms of such interplay differ among participants of LLFS and other studies. To address these questions, we evaluated associations with AD of interactions between genetic variants (SNPs) located in DNA encoding miR-107 and NLRP3 in participants of the LLFS and Framingham Heart Study using a logistic regression model with an interaction term. The facts that both datasets deal with data on related individuals and that many SNPs from either miR-107 or NLRP3 are in linkage disequilibrium were accounted for in these studies. The analysis of the Framingham data showed that the association with AD of the interaction between SNPs from miR-107 and the NLRP3 gene was statistically significant(p=6.71E-03; Bonferroni correction=7.14E-03). The association of the same interaction with AD was replicated in the analysis of LLFS data. These results indicate that in addition to regulating BACE1 expression and Aβ production, miR-107 may influence AD in interaction with the NLRP3 gene.

α7nAChR activation protects against oxidative stress, neuroinflammation and central insulin resistance in ICV-STZ induced sporadic Alzheimer's disease

Central insulin resistance is considered as one of the pathological hallmarks of Alzheimer's disease (AD), similar to formation of amyloid plaques and neurofibrillary tangles (NFT). Activation of α7nAChR by GTS-21 has been indicated to reverse peripheral insulin resistance and exert neuroprotection. Therefore, the aim of the present study was to determine the effect of α7nAChR agonist (GTS-21) on intracerebroventricular administration of streptozotocin (ICV-STZ)-induced oxidative stress, neuroinflammation, cholinergic dysfunction, central insulin resistance and cognitive deficits. GTS-21 (1, 4 and 8 mg/kg; i.p.) was administered for 21 days following bilateral ICV-STZ administration (3 mg/kg) in C57BL/6 mice. Neurobehavioral assessments were performed using Morris water maze (MWM) and novel object recognition (NOR). Inflammatory markers (TNF-α, IL-6 and IL-1β) were determined using ELISA. Oxido-nitrosative stress (GSH, MDA and nitrite) and cholinergic activity (acetylcholine esterase and choline acetyltransferase) were estimated in the cortex and hippocampus through biochemical methods. Gene expression of insulin receptor (IR), IRS1, IRS2, BACE1, APP, PI3-K, AKT and GSK3β were determined by q-RT-PCR. ICV-STZ administration induced memory impairment, increased oxidative stress and neuroinflammation, and caused cholinergic dysfunction. Our results demonstrated that activation of α7nAChR by GTS-21 treatment improved memory in MWM and NOR test. Moreover, GTS-21 treatment significantly decreased oxido-nitrosative stress, inflammatory markers and cholinergic dysfunction in cortex and hippocampus. Finally, GTS-21 treatment restored ICV-STZ induced downregulation of IR, IRS1, IRS2, PI3-k, Akt and attenuated GSK3β, APP and BACE-1 indicating improved insulin signalling. Therefore, activation of α7nAChR through GTS-21 might be the potential target for the amelioration of central insulin resistance induced AD.

Dual Role of Phenyl Amides from Hempseed on BACE 1, PPARγ, and PGC-1α in N2a-APP Cells.

In Alzheimer’s disease (AD) the accumulation of amyloid β (Aβ) plaques in the brain leads to neuroinflammation, neuronal cell dysfunction, and progressive memory loss. Therefore, blocking the formation of Aβ plaques has emerged as one of the most promising strategies to develop AD treatments. Hempseed is widely used as a food, and recently its compounds have shown beneficial effects on neuroinflammation. The objective of this study was to investigate whether a fraction rich in phenyl amide compounds, N-trans-caffeoyltyramine (CAFT) and N-trans-coumaroyltyramine (CUMT), can affect gene expression: β-site amyloid-precursor-protein-cleaving enzyme 1 (BACE 1), peroxisome proliferator-activated receptor gamma (PPAR γ), and PPARγ-coactivator-1α (PGC-1α) in N2a-APP cells. The mRNA levels were measured using RT-qPCR. The ethyl acetate fraction and CAFT were found to reduce BACE1 gene expression and are promissory PPARγ and PGC-1α natural agonists. The results show that hempseed compounds can inhibit the expression of BACE 1, which is involved in the accumulation of Aβ plaques and positively affect transcription factors involved in complex and diverse biological functions.

Crocin mitigated cognitive impairment and brain molecular alterations induced by different intensities of prenatal hypoxia in neonatal rats.

IntroductionBrain hypoxia has important role to the onset and progression of sporadic form of Alzheimer disease via expression of hypoxia‐inducible factor‐1 (HIF‐1). Crocin by anti‐amyloidogenic property inhibits β‐amyloid formation. However, the molecular mechanism associated with anti‐amyloidogenic activity of crocin is unknown. So, the present study was designed to investigate the effect of crocin on cognitive behavior and expression of HIF‐1α and β‐secretase (BACE1) genes in the brain of neonate rats following different intensities of hypoxia during pregnancy.Material and methodsPregnant female rats were divided into six groups including sham, control crocin treated (CC), hypoxia with three different intensities (H1–H3), and most intense of hypoxic group treated with crocin (H3C) (30 mg/kg; i.p) at P14. Hypoxia induced on the 20th day of pregnancy. Animals in sham and CC were put in hypoxia chamber at the same time of hypoxia group without any hypoxia induction. Morris water maze (MWM) and qRT‐PCR were used to evaluate the cognitive behavior and mRNA levels of BACE1 and HIF‐1α genes in the brain tissues.ResultsAnimal under 7% O2 + 93% N2 condition for 3 hr showed the highest cognitive behavior impairment and upregulated HIF‐1α and BACE1 mRNA in brains of offspring (p < .001). Crocin treatment improved memory impairment and attenuated the gene expression of HIF‐1α and BACE1 in the brains of neonate rat.ConclusionsIt was concluded that crocin has beneficial effects on the brain of neonate rats under gestational hypoxia by improvement of memory impairment and molecular alteration related to hypoxia.

Manganese Exposure Aggravates β-Amyloid Pathology by Microglial Activation

Human epidemiological evidence and animal experimental data suggest that chronic manganese (Mn) exposure increases the risk of Alzheimer’s disease (AD) and amyloid plaques, a hallmark of AD brain pathology, but the underlying mechanisms were not fully understood. Using the transgenic APP/PS1/Tau triple transgenic AD (3×Tg-AD) mouse model and mouse-derived microglia and neuroblastoma cell lines, we found that chronic 5-month Mn treatment increased beta amyloid peptide (Aβ) expression and Aβ plaques in the cerebral cortex and hippocampus in these 3×Tg-AD mice. Furthermore, we found that the β- and γ-secretase cleavage activities were markedly increased, while α-secretase cleavage activity was reduced in the brain of Mn-treated AD mice; these effects increase Aβ production and thus are amyloidogenic. Equally important, Mn treatment alone did not alter β-secretase 1 (BACE1) gene expression or Aβ production in amyloidogenic mutant amyloid precursor protein (APP) gene hAPPsw-transfected N2a cells (APPsw-N2a), but in APPsw-N2a cells either co-cultured with microglia or cultured with microglia-conditioned media, Mn exposure increased BACE1 expression and amyloidogenesis. We further determined that Mn exposure promoted the activation of microglia both in 3×Tg-AD mouse brains and in cultured microglia cells, and increased the secretion of the inflammatory cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Taken together, these results suggest that Mn may increase the release of IL-1β and TNF-α from microglia that in turn stimulates the expression of BACE1 gene and protein and consequently Aβ production; this novel molecular mechanism not only advances our understanding about the amyloidogenic effect of chronic Mn exposure reported for special human populations but also indicates Mn dyshomeostasis as a potential contributor to AD pathogenesis.

Exercise-mediated alteration of hippocampal Dicer mRNA and miRNAs is associated with lower BACE1 gene expression and Aβ1-42 in female 3xTg-AD mice

Changes to cerebral miRNA expression have been implicated in the progression of Alzheimer's disease (AD), as miRNAs that regulate the expression of gene products involved in amyloid beta (Aβ) processing, such as BACE1, are dysregulated in those that suffer from AD. Exercise training improves cognition and reduces BACE1 and Aβ-plaque burden; however, the mechanisms are not fully understood. Using our progressive weighted wheel running (PoWeR) exercise program, we assessed the effect of 20 wk of exercise training on changes in hippocampal miRNA expression in female 3xTg-AD (3xTg) mice. PoWeR was sufficient to promote muscle hypertrophy and increase myonuclear abundance. Furthermore, PoWeR elevated hippocampal Dicer gene expression in 3xTg mice, while altering miRNA expression toward a more wild-type profile. Specifically, miR-29, which is validated to target BACE1, was significantly lower in sedentary 3xTg mice when compared with wild-type but was elevated following PoWeR. Accordingly, BACE1 gene expression, along with detergent-soluble Aβ1-42, was lower in PoWeR-trained 3xTg mice. Our data suggest that PoWeR training upregulates Dicer gene expression to alter cerebral miRNA expression, which may contribute to reduced Aβ accumulation and delay AD progression.NEW & NOTEWORTHY Previous studies have outlined the beneficial effects of exercise on lowering BACE1 expression and reducing Aβ plaques. This study extends upon the work of others by outlining a new potential mechanism by which exercise elicits beneficial effects on Alzheimer's disease pathology, specifically through modulation of Dicer and miRNA expression. This is the first study to examine Dicer and miRNA expression in the hippocampus of the 3xTg model within the context of exercise.

Effect of memantine on expression of Bace1-as and Bace1 genes in STZ-induced Alzheimeric rats.

Recent studies have showed that the long non-coding RNAs (lncRNAs) expression is dysregulated in different neurodegenerative disorders like Alzheimer's disease (AD). In the present study, the effects of memantine on the level of Bace1-as and Bace1 genes' expression in streptozotocin (STZ)-induced Alzheimer's and memantine treated rats were investigated. The male Wistar rats were randomly divided into four groups: 1-Normal control, 2-Sham-operated control, 3- Alzheimer'scontrol rats (ICV-STZ), 4-Experimental group rats treated by memantine in a dose of 30mg/kg/day for 28days in ICV-STZ rats. The expression of Bace1-as and Bace1 genes was measured by quantitative-PCR in the brain and blood tissues. ELISA was used to analyze Bace1 and Aβ proteins. Expression of Bace1-as was significantly increased in the brain and blood tissues of the experimental group (p = 0.032 and p = 0.034, respectively). The expression of Bace1 gene showed no significant changes in the brain. Furthermore, the ELISA analysis revealed that Bace1 protein was significantly increased in the plasma of the Alzheimer's control group (p = 0.000) and in the brain tissue of the experimental group (p = 0.000). Additionally, Aβ levels had no significant changes between all groups studied. The Bace1 protein may be used as a prognostic biomarker in plasma, or before using memantine as a treatment. Furthermore, Bace1-as gene expression may play a role in monitoring the progression of AD.

Using the Allen gene expression atlas of the adult mouse brain to gain further insight into the physiological significance of TAG-1/Contactin-2.

The anatomic gene expression atlas (AGEA) of the adult mouse brain of the Allen Institute for Brain Science is a transcriptome-based atlas of the adult C57Bl/6J mouse brain, based on the extensive in situ hybridization dataset of the Institute. This spatial mapping of the gene expression levels of mice under baseline conditions could assist in the formation of new, reasonable transcriptome-derived hypotheses on brain structure and underlying biochemistry, which could also have functional implications. The aim of this work is to use the data of the AGEA (in combination with Tabula Muris, a compendium of single cell transcriptome data collected from mice, enabling direct and controlled comparison of gene expression among cell types) to provide further insights into the physiology of TAG-1/Contactin-2 and its interactions, by presenting the expression of the corresponding gene across the adult mouse brain under baseline conditions and to investigate any spatial genomic correlations between TAG-1/Contactin-2 and its interacting proteins and markers of mature and immature oligodendrocytes, based on the pre-existing experimental or bibliographical evidence. The across-brain correlation analysis on the gene expression intensities showed a positive spatial correlation of TAG-1/Contactin-2 with the gene expression of Plp1, Myrf, Mbp, Mog, Cldn11, Bace1, Kcna1, Kcna2, App and Nfasc and a negative spatial correlation with the gene expression of Cspg4, Pdgfra, L1cam, Ncam1, Ncam2 and Ptprz1. Spatially correlated genes are mainly expressed by mature oligodendrocytes (like Cntn2), while spatially anticorrelated genes are mainly expressed by oligodendrocyte precursor cells. According to the data presented in this work, we propose that even though Contactin-2 expression during development correlates with high plasticity events, such as neuritogenesis, in adulthood it correlates with pathways characterized by low plasticity.

The impact of capsaicinoids on APP processing in Alzheimer\u2019s 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.

Expression of Bace1 is positive with the progress of atherosclerosis and formation of foam cell

Previous studies have shown that the occurrence of atherosclerosis is closely related to changes of α2, 6-sialic acid transferase I (ST6Gal-I). Bace1 has been identified as a protease responsible for the cleavage and secretion of Golgi-resident ST6Gal-I. There have been only a few attempts to clarify the direct connection between Bace1 and atherosclerosis. The purpose of this study was to investigate the relationship between Bace1 gene and atherosclerosis. Expressions of Bace1 protein and mRNA in ApoE−/− mice fed on high-fat diet were evaluated and the development of atherosclerosis was assessed in Bace1−/− mice fed on high-fat diet. In vitro, the expression of Bace1 gene was detected in foam cell model and the formation of foam cells was examined after knocking down Bace1 by siRNA. We observed a significant increase in Bace1 expression in the aortic root in the model of atherosclerosis in ApoE−/−mice. The expression of Bace1 protein and mRNA levels had a remarkable increase in high-fat group. After knocking out the Bace1 gene, serum lipid levels were significantly lower and intimal thickness was obvious thinner than those in wild-type mice with high-fat diet. Expression of Bace1 protein and mRNA levels were significantly elevated in foam cell. The formation of foam cells was blocked when Bace1 was knocked down by siRNA interferes. Our results suggested that elevated Bace1 gene had a positive role in the progression of atherosclerosis. Affecting the glycosyltransferase may be one of its mechanisms.

BDNF‐Induced Arc Expression Was Enhanced by PIC in Neuronal Cells Treated with High Glucose and Amyloid Beta

ObjectivesHyperglycemia has been shown to be associated with Alzheimer’s disease and impairment of cognitive function. Alzheimer’s disease is characterized by the excessive formation of amyloid‐beta (Aβ) and neurofibrillary tangle. Aβ is generated by cutting amyloid precursor protein (APP) by β‐secretase (BACE1) and γ‐secretase. Brain‐derived neurotrophic factor (BDNF) is the important molecule that is involved in synaptic plasticity and neuronal survival. BDNF binds to trkB receptor and activates PI3K/Akt/mTOR pathway, and it increases synaptic efficacy by inducing expression of activity‐regulated cytoskeleton‐associated protein (Arc) which is the marker of plastic changes of the brain. Suppression of BDNF is related to the pathogenesis of Alzheimer’s disease. Piceatannol (PIC) is a polyphenolic compound that has similar structure to resveratrol having neuroprotective efficacy. Thus, we investigated the effects of PIC treatment on amyloidogenesis and BDNF signaling in neuronal cells treated with high glucose and Aβ.MethodsThe SH‐SY5Y cells were treated with 25 mM D‐glucose and 10 μM Aβ in order to induce the cell culture model of high glucose‐induced Alzheimer’s disease. And then, cells were treated with 20 μM PIC for 24 h. Relative gene expression levels of amyloidogenesis‐ and BDNF signaling‐related markers were analyzed. Aβ concentrations were measured by ELISA to examine whether PIC alters the levels of Aβ deposit. One‐way analysis of variance (ANOVA) was performed to assign statistical significance followed by Fisher’s Least Significant Difference (LSD) post‐hoc analysis using SPSS software (IBM SPSS Statistics 24).ResultsIn the condition of high glucose‐induced Alzheimer’s disease, PIC treatment significantly increased the relative gene expression of BACE1 (P = 0.003). The presenilin 1 expression tended to rise up by PIC in this condition. The concentrations of Aβ were significantly lower in cells treated with high glucose, Aβ, and PIC compared with those without PIC (P &lt; 0.001). The relative expression levels of BDNF in high glucose group treated with PIC tended to be higher than those without PIC. PIC treatment significantly increased the relative gene expression of BDNF in cells treated with high glucose and Aβ (P = 0.002). The Arc expression was also significantly increased by PIC in those cells (P = 0.038).ConclusionsWe found that PIC improves the pathological alterations by high glucose and Aβ, which is accompanied by decreased Aβ formation and upregulation of BDNF and Arc expressions in high glucose and Aβ‐treated neuronal cells. Therefore, PIC may have a therapeutic effect on the pathological conditions of hyperglycemia‐induced Alzheimer’s disease.

Crocin Treatment after Maternal Hypoxia Attenuates Spatial Memory Impairment and Expression of BACE1 and HIF-1α in Rat Offspring Brain.

Introduction:Hypoxia via expression of Hypoxia-Inducible Factor-1 (HIF-1) is an important and effective factor in the onset and progression of memory disorders, such as Alzheimer Disease (AD). The activity of β-secretase (BACE1) is increased in hypoxia conditions. BACE1 triggers a cascade of pathological events resulting in AD. Crocin acts as a memoryimproving agent but its molecular mechanism is not well-known. Therefore, in this study, the effect of crocin on spatial memory, HIF-1α, and BACE1 gene expression was investigated in rat offspring under maternal hypoxia.Methods:Female pregnant rats on the 20th day of pregnancy were divided into 4 groups, including sham, crocin-treated, hypoxia, and hypoxia group treated with crocin. In the hypoxia groups, pregnant rats were exposed to 7% oxygen and 93% nitrogen intensity for 3 h. In the crocin-treated group, crocin (30 mg/kg) was injected at P14–28 (i.p). At the end, Morris water maze was used to assess spatial memory and real-time polymerase chain reaction was performed to measure the expression of BACE1 and HIF-1α genes in the brain of offspring.Results:Maternal hypoxia impaired memory compared with the sham group. However, crocin treatment improved cognitive behavior. HIF-1α and BACE1 expressions were upregulated in the brain of offspring in the hypoxia group. Crocin treatment could attenuate the expression of both genes.Conclusion:According to our results, down-regulation of HIF-1α and BACE1 gene expressions in the brain of rat offspring after crocin treatment can be suggested as a molecular mechanism for crocin to improve spatial memory.

Curcumin inhibits BACE1 expression through the interaction between ERβ and NFκB signaling pathway in SH-SY5Y cells.

Alzheimer's disease (AD) is the leading cause of dementia, which characterized by toxic senile plaques is composed of amyloid-β (Aβ). β-site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting protease in Aβ generation. Therefore, pharmacology BACE1 inhibition is one of the prime targets for potential treatment of AD. Curcumin, a yellow polyphenol derived from the rhizomes of the plant Curcuma longa Linn, has been reported to cross the blood-brain barrier and prevent Aβ aggregation in AD models. However, its neuroprotective mechanism is still unclear. In the present study, we find that curcumin markedly reduces Aβ levels in HEK293-APPswe cells. Our results show that curcumin inhibits BACE1 gene expression in SH-SY5Y cells at transcriptional and translational levels. Furthermore, we reveal that nuclear factor kappa B (NFκB) signaling is involved in the regulation of curcumin on BACE1. Interestingly, the estrogenicity of curcumin is found to partially contribute to its protective action. Our data show that curcumin activates estrogen receptor β (ERβ) selectively and the activation of ERβ directly effects on the upstream factors of the NFκB signaling pathway. The above results indicate that curcumin reduces BACE1 expression through ERβ and NFκB pathway, providing a novel mechanism for curcumin as a candidate for AD therapy.

Gestational high fat diet protects 3xTg offspring from memory impairments, synaptic dysfunction, and brain pathology.

Maternal history for sporadic Alzheimer’s disease (AD) predisposes the offspring to the disease later in life. However, the mechanisms behind this phenomenon are still unknown. Lifestyle and nutrition can directly modulate susceptibility to AD. Herein we investigated whether gestational high fat diet influences the offspring susceptibility to AD later in life. Triple transgenic dams were administered high-fat diet or regular chow throughout 3 weeks gestation. Offspring were fed regular chow throughout their life and tested for spatial learning and memory, brain amyloidosis, tau pathology and synaptic function. Gestational high fat diet attenuated memory decline, synaptic dysfunction, amyloid-β and tau neuropathology in the offspring by transcriptional regulation of BACE-1, CDK5 and tau gene expression via the up-regulation of FOXP2 repressor. Gestational high fat diet protects offspring against the development of the AD phenotype. In-utero dietary intervention could be implemented as preventative strategy against AD.

A gender dimorphism in up-regulation of BACE1 gene expression in schizophrenia.

Schizophrenia has long been considered as a devastating brain disorder in which both genetic and environmental factors are involved. The BACE1 gene is one of the most important susceptibility genes for this disorder. However, the changes in BACE1 expression in schizophrenic patients compared with healthy subjects have not been evaluated yet. In this case-control study, we examined BACE1 expression in a group of 50 patients with schizophrenia and 50 healthy controls. The level of BACE1 gene expression was measured using Real-Time PCR. Substantial increase in gene expression was detected in the patients compared with normal individuals (P= 0.001). Furthermore, a gender dimorphism was observed in BACE1 gene expression in the patients in a way that the male patients manifested a statistically significant higher levels of BACE1 expression (P= 0.002). BACE1 might be implicated in the pathogenesis of schizophrenia. Besides, BACE1 physiology may be gender -based at some levels. Our findings warrant an investigation of BACE1 gene in a larger number of cases and controls.

Aluminum-induced molecular neurodegeneration: The protective role of genistein and chickpea extract

Neurotoxicity of Al is well established and linked to oxidative damage and neurodegeneration. This study investigated the protective role of genistein (Gen) and chickpea extract (CPE) against AlCl3-induced neurodegeneration. HPLC analysis revealed that biochanin A-7-O-β-D-glucoside and biochanin A are the major components of the CPE. Gene expression of TNF-α, APP, BACE1, PSEN-2 and ER-β were assessed in brain extract using RT-PCR. Also, NF-кB subunit P65 and COX-2 expression were evaluated by western blotting. The cholinergic function, histological examination and oxidative status were also estimated. The AlCl3 significantly up regulated the expression of the NF-кB subunit P65, COX-2, TNF- α, BACE1and APP while it significantly down regulated PSEN-2 and ER-β expression. The activity of acetyl cholinesterase (AChE) and the oxidative stress parameters as well as the histological examination confirmed the deleterious effect of AlCl3. The administration of either CPE or Gen attenuated the expression of inflammatory cytokines, inhibited the amyloidogenesis and restored both the AChE activity and ER-β expression. Gen and CPE also inhibited the oxidative stress and ameliorated the histological alterations. Accordingly, the present study provides an insight on the molecular role of Gen and CPE as protective agents against neuronal injury.

Maternal Vitamin B Deficiency and Epigenetic Changes of Genes Involved in the Alzheimer’ s Disease Pathogenesis

Alzheimer's disease (AD) is characterized by progressive neurodegenerative impairment of the central nervous system and is the most prevalent form of dementia. Considering the influence of maternal nutrition on fetal programming, which consequences usually come later in life, we investigated whether maternal vitamin B deficiency during early development alters the offspring expression of genes related to AD etiopathogenesis. Mice dams were submitted to experimental diet one month before and during pregnancy or pregnancy/lactation and, after birth, their offspring were distributed into three groups: control “CT”, deficient pregnancy “DP” and deficient pregnancy and lactation “DPL”. At postnatal day (PND) 0, a significant decrease of App in females (p=0.007) and App and Bace1 in males (p=0.030 and p=0.040, respectively) was observed when compared to CT group. At PND 28, DPL female presented an increase of App, Bace1 and Ps1 gene expression when compared to CT (p=0.003, p=0.003 and p=0.002, respectively) and DP groups (p=0.017, p=0.005 and p=0.002, respectively). In males at PND 28, a decrease of App and Ps1 was observed in both DP (p=0.012; p=0.001) and DPL (p=0.001; p=0.04) when compared to CT group. No differences were observed in females and males at PND 210. Regarding APP, BACE1 and PS1 protein expression and global DNA methylation pattern, no difference was observed throughout development in female or male offspring. Regarding behavioral evaluations, no changes were observed in the object recognition task, but the DPL males presented lower locomotor activity when compared to DP (p=0.028) and CT (p=0.003) groups. In conclusion, the early exposition to vitamin B deficiency alters the expression of genes related to AD.