Non-coding RNAs are involved in tumor cell death and affect tumorigenesis, progression, and treatment: a systematic review.

Cell death is ubiquitous during development and throughout life and is a genetically determined active and ordered process that plays a crucial role in regulating homeostasis. Cell death includes regulated cell death and non-programmed cell death, and the common types of regulatory cell death are necrosis, apoptosis, necroptosis, autophagy, ferroptosis, and pyroptosis. Apoptosis, Necrosis and necroptosis are more common than autophagy, ferroptosis and pyroptosis among cell death. Non-coding RNAs are regulatory RNA molecules that do not encode proteins and include mainly microRNAs, long non-coding RNAs, and circular RNAs. Non-coding RNAs can act as oncogenes and tumor suppressor genes, with significant effects on tumor occurrence and development, and they can also regulate tumor cell autophagy, ferroptosis, and pyroptosis at the transcriptional or post-transcriptional level. This paper reviews the recent research progress on the effects of the non-coding RNAs involved in autophagy, ferroptosis, and pyroptosis on tumorigenesis, tumor development, and treatment, and looks forward to the future direction of this field, which will help to elucidate the molecular mechanisms of tumorigenesis and tumor development, as well as provide a new vision for the treatment of tumors.

Progress in research on tumor microenvironment-based spatial omics technologies.

Spatial omics technology integrates the concept of space into omics research and retains the spatial information of tissues or organs while obtaining molecular information. It is characterized by the ability to visualize changes in molecular information and yields intuitive and vivid visual results. Spatial omics technologies include spatial transcriptomics, spatial proteomics, spatial metabolomics, and other technologies, the most widely used of which are spatial transcriptomics and spatial proteomics. The tumor microenvironment refers to the surrounding microenvironment in which tumor cells exist, including the surrounding blood vessels, immune cells, fibroblasts, bone marrow-derived inflammatory cells, various signaling molecules, and extracellular matrix. A key issue in modern tumor biology is the application of spatial omics to the study of the tumor microenvironment, which can reveal problems that conventional research techniques cannot, potentially leading to the development of novel therapeutic agents for cancer. This paper summarizes the progress of research on spatial transcriptomics and spatial proteomics technologies for characterizing the tumor immune microenvironment.

The miR-203a Regulatory Network Affects the Proliferation of Chronic Myeloid Leukemia K562 Cells.

To study the molecular mechanism by which miR-203a affects the development of CML, bioinformatics software was used to predict the upstream transcription factors and downstream target genes of miR-203a. A 5'-rapid amplification of cDNA ends assay was performed to detect gene transcription initiation sites. A chromatin immunoprecipitation assay was used to verify the binding of transcription factors and promoter regions. A double luciferase reporter gene vector was constructed to demonstrate the regulatory effect of miR-203a on target genes. Real-time PCR and western blotting were used to detect the relative expression levels of genes and proteins, respectively. The results showed that there was a binding site for the transcription factor EGR1 in the upstream promoter region of miR-203a. WT1, BMI1, and XIAP were identified as target genes regulated by miR-203a. EGR1 and miR-203a were downregulated in human peripheral blood mononuclear cells and the CML K562 cell line, while WT1, BMI1, and XIAP were upregulated. The transcription initiation site of miR-203a was identified in the upstream promoter region (G nucleotide at -339 bp), and the transcription factor EGR1 could bind to the promoter region (at -268 bp) of miR-203a and increase its expression. Over expression of miR-203a inhibited the proliferation of K562 cells. A rescue assay showed that overexpression of WT1, BMI1, and XIAP offset the antitumor effect of miR-203a. Conclusion, EGR1 positively regulated the expression of miR-203a, thus relieving the inhibition of miR-203a on the translation of its target genes (WT1, BMI1, and XIAP) and affecting the proliferation of K562 cells.

The efficacy and safety of auricular point combined with moxibustion for insomnia: A protocol for systematic review and meta-analysis.

BACKGROUND: Insomnia is a common sleep disorder, which seriously affects people's quality of life and work ability. In China, auricular therapy and moxibustion therapy have a long history in treating insomnia. Clinical studies have shown that auricular point and moxibustion can effectively improve insomnia symptoms. At present, auricular point combined with moxibustion in the treatment of insomnia has been widely used in China, but its overall effectiveness and safety are still unclear. There is a lack of systematic evaluation of auricular point combined with moxibustion in the treatment of insomnia. This paper aims to evaluate the efficacy and safety of auricular point combined with moxibustion in the treatment of insomnia. METHODS: Retrieve randomized controlled trials of auricular point combined with moxibustion from PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure, WanFang, the Chongqing VIP Chinese Science and Technology Periodical Database, and China biomedical literature database from their establishment to August 2020. Search Baidu Scholar, Google Scholar, International Clinical Trials Registry Platform, and Chinese Clinical Trials Registry for unpublished gray literature. Two researchers independently applied RevMan 5.3 software for data extraction and risk assessment of bias. RESULTS: This study evaluated the efficacy and safety of auricular point combined with moxibustion in the treatment of insomnia from Pittsburgh sleep quality index, Rhone planck sleepiness scale, Traditional Chinese medicine syndrome scores, Hamilton anxiety scale (HAMA), Hamilton Depression, 5-hydroxytryptamine, incidence of adverse reactions, and other aspects. CONCLUSION: This study will provide theoretical support for the clinical application of auricular point combined with moxibustion in the treatment of insomnia. ETHICS AND DISSEMINATION: The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/8VZRJ.

Efficacy and safety of traditional Chinese herbal formula combined with western medicine for uterine fibroid: A protocol for systematic review and meta-analysis.

BACKGROUND: Clinical studies found that the combination of traditional Chinese herbal formula, and western medicine therapy are better in shrinking fibroids and improve other symptoms. This study aims to systematically evaluate the efficacy and safety traditional Chinese herbal formula combined with western medicine in the treatment of uterine fibroids. METHODS: Randomized controlled trials of traditional Chinese herbal formula combined with western medicine for uterine fibroids patients will be searched in PubMed, Medline, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Chongqing VIP Chinese Science and Technology Periodical Database, Chinese Biological and Medical database (CMB), and Wanfang database from inception to August 2020. Two researchers will perform data extraction and risk of bias assessment independently. Statistical analysis will be conducted in RevMan 5.3. RESULTS: This study will summarize the present evidence by exploring the efficacy and safety of traditional Chinese herbal formula combined with western medicine in the treatment of uterine fibroids CONCLUSIONS:: The findings of the study will help to determine potential benefits of traditional Chinese herbal formula combined with western medicine in the treatment of uterine fibroids. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/XUA8V.

Small interfering RNA target for long noncoding RNA PCGEM1 increases the sensitivity of LNCaP cells to baicalein.

The objective of this study is to investigate the inhibitory effect and mechanism of long noncoding RNA PCGEM1 siRNA combined with baicalein on prostate cancer LNCaP cells. LNCaP cells transfected with small hairpin RNA lentiviral vector targeting PCGEM1 were constructed and their expression in LNCaP cells was absent. The stable cell line of LNCaP cells infected with LV3-shRNA-PCGEM1 was successfully constructed. In addition, LV3-shRNA-PCGEM1 was able to increase the baicalein-induced inhibitory effects on LNCaP cells, and the susceptibility was 2.3 fold higher than that of baicalein alone. LV3-shRNA-PCGEM1 combined with baicalein also inhibited the colony formation, increased G2 and S phase cells, inhibited the expression of PCGEM1, and induced autophagy of LNCaP cells. In summary, LV3-shRNA-PCGEM1 may improve the sensitivity of LNCaP cells to baicalein, and the molecular mechanism may be associated with the decrease of PCGEM1 expression and the induction of autophagy. Our findings provided an experimental basis for the combined treatment of Chinese traditional and Western medicine on prostate cancer in a clinical setting.

hsa_circ_0006459 and hsa_circ_0015962 affect prognosis of Dengue fever.

Circular ribonucleic acids (circRNAs) are widely expressed in human cells and play an important role in the pathogenesis of many diseases. Some circRNAs have microRNA (miRNA) binding response elements and interact with miRNA to regulate the expression of target genes.Four patients with a preliminary diagnosis of dengue fever (DF), peripheral whole blood sample in anticoagulant was collected before treatment (pretreatment group) and after effective treatment (posttreatment group), and eight samples were separated and used to screen differentially expressed circRNAs with microarray analysis. The relative expression level of circRNAs was determined using reverse-transcription polymerase chain reaction (RT-PCR). TargetScan v7.1 and miRDB v5 bioinformatics software were used to predict circRNA-binding miRNAs; dual luciferase reporters were constructed to detect binding between circRNA and miRNA. Microarray screening revealed 263 differentially expressed circRNAs in peripheral leukocytes pretreatment versus posttreatment; 107 of these were upregulated and 156 were downregulated. RT-PCR confirmed that hsa_circ_0015962 was significantly upregulated and hsa_circ_0006459 significantly downregulated (P < 0.05). Moreover, hsa_circ_0015962 binds to miR-4683, and hsa_circ_0006459 binds to miR-133b.Downregulation of hsa_circ_0006459 and upregulation of hsa_circ_0015962 affect the treatment response of DF and are potential biomarkers in DF patients. The molecular mechanism involves hsa_circ_0006459-mediated targeted negative regulation of miR-133b and hsa_circ_0015962-mediated targeted negative regulation of miR-4683.

Synthesis and anticancer activity of novel rapamycin C-28 containing triazole moiety compounds.

Rapamycin is an mTOR allosteric inhibitor with multiple functions such as immunosuppressive, anticancer, and lifespan prolonging activities. Its C-43 semi-synthetic derivatives temsirolimus and everolimus have been used as mTOR targeting anticancer drugs in the clinic. Following our previous research on antitumor rapalogs modified on the C-43 position, 13 novel rapamycin triazole hybrids (6a-g, 7a-f) were designed and synthesized on the C-28 position of rapamycin via Huisgen's reaction. Anticancer assays indicated that the targeted derivatives containing phenyl and 4-methylphenyl groups showed an obvious raise in anticancer activity. On the contrary, the compounds with methoxyl, amine, and halogen groups on the benzene ring displayed lower anticancer activity. Compound 6c, as the most active compound, showed a stronger inhibition effect as compared with rapamycin for almost all of the tested cell lines (p < 0.01), except PC-3. Meanwhile, the effect of 6c on inducing apoptosis and cell cycle arrest in A549 cells was more powerful than that of rapamycin. In addition, 6c inhibited the phosphorylation of mTOR and its downstream key kinases 4EBP1 and p70S6K1 in A549 cells, indicating that 6c also effectively inhibits the mTORC1 signaling pathway as rapamycin. On the basis of these findings, 6c may have the potential to be developed as a new mTOR inhibitor against specific cancers.

The CircRNA-ACAP2/Hsa-miR-21-5p/ Tiam1 Regulatory Feedback Circuit Affects the Proliferation, Migration, and Invasion of Colon Cancer SW480 Cells.

BACKGROUND/AIMS: Circular RNAs (circRNAs), a type of RNA that is widely expressed in human cells, have essential roles in the development and progression of cancer. CircRNAs contain microRNA (miRNA) binding sites and can function as miRNA sponges to regulate gene expression by removing the inhibitory effect of an miRNA on its target gene. METHODS: We used the bioinformatics software TargetScan and miRanda to predict circRNA-miRNA and miRNAi-Mrna interactions. Rate of inhibiting of proliferation was measured using a WST-8 cell proliferation assay. Clone formation ability was assessed with a clone formation inhibition test. Cell invasion and migration capacity was evaluated by performing a Transwell assay. Relative gene expression was assessed using quantitative real-time polymerase chain reaction and relative protein expression levels were determined with western blotting. circRNA and miRNA interaction was confirmed by dual-luciferase reporter and RNA-pull down assays. RESULTS: In the present study, the miRNA hsa-miR-21-5p was a target of circRNA-ACAP2, and T lymphoma invasion and metastasis protein 1 (Tiam1) was identified as a target gene of hsa-miR-21-5p. CircRNA-ACAP2 and Tiam1 were shown to be highly expressed in colon cancer tissue and colon cancer SW480 cells, but miR-21-5p was expressed at a low level. SW480 cell proliferation was suppressed when the expression of circRNA-ACAP2 and Tiam1 was decreased and the expression of miR-21-5p was increased in vivo and in vitro. SW480 cell migration and invasion were also inhibited under the same circumstance. The circRNA-ACAP2 interaction regulated the expression of miR-21-5p, and miR-21-5p regulated the expression of Tiam1. Down-regulation of circRNA-ACAP2 promoted miR-21-5p expression, which further suppressed the transcription and translation of Tiam1. CONCLUSION: The present study shows that the circRNA-ACAP2/hsa-miR-21-5p/Tiam1 regulatory feedback circuit could affect the proliferation, migration, and invasion of colon cancer SW480 cells. This was probably due to the fact that circRNA-ACAP2 could act as a miRNA sponge to regulate Tiam1 expression by removing the inhibitory effect of miR-21-5p on Tiam1 expression. The results from this study have revealed new insights into the pathogenicity of colon cancer and may provide novel therapeutic targets for the treatment of colon cancer.

MiR-145 affected the circular RNA expression in prostate cancer LNCaP cells.

Recent evidence has demonstrated that circular RNAs (circRNAs) played crucial roles in fine-tuning the levels of gene expression by sequestering the corresponding microRNA (miRNAs). Their interaction with disease-associated miRNAs indicates that circRNAs are important for the development of disease, and miR-145 has been previously shown to have antitumor effect in prostate cancer. In the current study, we successfully established the miR-145-overexpressed prostate cancer LNCaP cells (LNCaP-miR-145) using lentiviral vectors. LNCaP cells expressing the empty vector (LNCaP-NC) were used as the negative control. The circRNA expression in LNCaP-miR-145 cells was detected by microarray analysis, and the miRNA targets of circRNAs were predicted using the bioinformatics software TargetScan and miRanda. Quantitative reverse transcription polymerase chain reaction was used to detect the expression levels of circRNAs in the prostate cancer tissue, nonmalignant tissue, LNCaP-miR-145 cells, and LNCaP-NC cells. The interaction of miRNA and circRNA was further confirmed by the dual-luciferase reporter assay. A total of 267 and 149 circRNAs were significantly up- and downregulated in LNCaP-miR-145 cells, respectively. hsa_circRNA_101981, hsa_circRNA_101996 and hsa_circRNA_09142 were the 3 circRNAs that interacted with hsa-miR-145-5p; hsa_circRNA_008068 and hsa_circRNA_406557 were the 2 circRNAs that interacted with hsa-miR-145-3p. Most of the circRNAs corresponded to the protein-coding exons. The expression levels of hsa_circRNA_101981, hsa_circRNA_00806, and hsa_circRNA_406557 were upregulated in the LNCaP-miR-145 cells, but downregulated in the prostate cancer tissue. In contrast, the expression levels of hsa_circRNA_101996 and hsa_circRNA_091420 were downregulated in the LNCaP-miR-145 cells, but upregulated in the prostate cancer tissue. Moreover, miR-145-5P might regulate the expression of hsa_circRNA_101981, hsa_circRNA_101996, and hsa_circRNA_09142, while miR-145-3P might regulate the expression of hsa_circRNA_008068 and hsa_circRNA_406557. Overexpression of miR-145 promoted the expression of hsa_circRNA_101981, hsa_circRNA_008068, and hsa_circRNA_406557 but suppressed the expressions of hsa_circRNA_101996 and hsa_circRNA_091420 in LNCaP cells. The results from the current study should give us a clue to clarify the tumor suppressive effect of miR-145.

Bioinformatic analysis and prediction of the function and regulatory network of long non-coding RNAs in hepatocellular carcinoma.

Computational analysis and bioinformatics have significantly advanced the ability of researchers to process and analyze biological data. Molecular data from human and model organisms may facilitate drug target validation and identification of biomarkers with increased predictive accuracy. The aim of the present study was to investigate the function of long non-coding RNAs (lncRNAs) in hepatocellular carcinoma (HCC) using online databases, and to predict their regulatory mechanism. HCC-associated lncRNAs, their downstream transcription factors and microRNAs (miRNAs/miRs), as well as the HCC-associated target genes, were identified using online databases. HCC-associated lncRNAs, including HOX antisense intergenic RNA (HOTAIR) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) were selected based on established databases of lncRNAs. The interaction between the HCC-associated lncRNAs and miRNAs (hsa-miR-1, hsa-miR-20a-5p) was predicted using starBase2.0. Signal transducer and activator of transcription 1, hepatocyte nuclear factor 4α (HNF4A), octamer-binding transcription factor 4, Nanog homeobox (NANOG), caudal type homeobox 2 (CDX2), DEAD-box helicase 5, brahma-related gene 1, MYC-associated factor X and MYC proto-oncogene, bHLH transcription factor have been identified as the transcription factors for HOTAIR and MALAT1 using ChIPBase. Additionally, CDX2, HNF4A, NANOG, ETS transcription factor, Jun proto-oncogene and forkhead box protein A1 were identified as the transcription factors for hsa-miR-1 and hsa-miR-20a-5p. CDX2, HNF4A and NANOG were the transcriptional factors in common between the lncRNAs and miRNAs. Cyclin D1, E2F transcription factor 1, epithelial growth factor receptor, MYC, MET proto-oncogene, receptor tyrosine kinase and vascular endothelial growth factor A were identified as target genes for the HCC progression, two of which were also the target genes of hsa-miR-1 and hsa-miR-20a-5p using the miRwalk and OncoDN. HCC databases. Additionally, these target genes may be involved in biological functions, including the regulation of cell growth, cell cycle progression and mitosis, and in disease progression, as demonstrated using DAVID clustering analysis. The present study aimed to predict a regulatory network of lncRNAs in HCC progression using bioinformatics analysis.

Gene-gene interaction network analysis of hepatocellular carcinoma using bioinformatic software.

Information processing tools and bioinformatics software have markedly advanced the ability of researchers to process and analyze biological data. Data from the genomes of humans and model organisms aid researchers to identify topics to study, which in turn improves predictive accuracy, facilitates the identification of relevant genes and simplifies the validation of laboratory data. The objective of the present study was to investigate the regulatory network constituted by long non-coding RNAs (lncRNAs), microRNAs (miRNAs) and mRNA in hepatocellular carcinoma (HCC). Microarray data from HCC datasets were downloaded from The Cancer Genome Atlas database, and the Limma package in R was used to identify the differentially expressed genes (DEGs) between HCC and normal samples. Gene ontology enrichment analysis of DEGs was conducted using the Database for Annotation, Visualization, and Integrated Discovery. TargetScan, microcosm, miRanda, miRDB and PicTar were used to predict target genes. lncRNAs associated with HCC were probed using the lncRNASNP database, and a lncRNA-miRNA-mRNA regulatory network was visualized using Cytoscape. The present study identified 114 differentially expressed miRNAs and 2,239 differentially expressed mRNAs; of these, 725 were downregulated genes that were primarily involved in complement and coagulation cascades, fatty acid metabolism and butanoate metabolism, among others. The remaining 1,514 were upregulated genes principally involved in DNA replication, oocyte meiosis and homologous recombination, among others. Through the integrated analysis of associations between different types of RNAs and target gene prediction, the present study identified 203 miRNA-mRNA pairs, including 28 miRNAs and 170 mRNAs, and identified 348 lncRNA-miRNA pairs, containing 28 miRNAs. Therefore, owing to the association between lncRNAs-miRNAs-mRNAs, the present study screened out 2,721 regulatory associations. The data in the present study provide a comprehensive bioinformatic analysis of genes, functions and pathways that may be involved in the pathogenesis of HCC.

Overexpression of Long Non-Coding RNA MEG3 Inhibits Proliferation of Hepatocellular Carcinoma Huh7 Cells via Negative Modulation of miRNA-664.

Evidence is accumulating that long non-coding RNAs (lncRNAs) are involved in human tumorigenesis and dysregulated in many cancers, including hepatocellular carcinoma (HCC). Because lncRNAs can regulate essential pathways that contribute to tumor initiation and progression with their tissue specificity, lncRNAs are valuable biomarkers and therapeutic targets. Maternally expressed gene 3 (MEG3) is a lncRNA overexpressed in HCC cells that inhibits HCC progression, however, the mechanism remains largely unknown. Recently, a novel regulatory mechanism has been proposed in which RNAs can cross-talk with each other via competing for shared microRNAs (miRNAs). The proposed competitive endogenous RNAs could mediate the bioavailability of miRNAs on their targets, thus imposing another level of post-transcriptional regulation. In the current study, we demonstrated that MEG3 is down-regulated in HCC tissues. MEG3 over-expression imposes another level of post-transcriptional regulation, whereas MEG3 overexpression increase the expression of the miR-664 target gene, ADH4, through competitive "sponging" miR-664. In addition, NF-κB may affect transcription of MEG3 by directly binding to the promoter region. Our data revealed that NF-κB may affect the transcript of MEG3. MEG3 overexpression inhibited the proliferation of HCC cells, at least in part by affecting miR-664mediated regulation of ADH4. Together, these results suggest that MEG3 is a suppressor of tumor which acts in part through "sponging" miR-664. J. Cell. Biochem. 118: 3713-3721, 2017. © 2017 Wiley Periodicals, Inc.

Snail-activated long non-coding RNA PCA3 up-regulates PRKD3 expression by miR-1261 sponging, thereby promotes invasion and migration of prostate cancer cells.

Rapidly accumulated evidence has shown that long non-coding RNA (lncRNAs) disregulation is involved in human tumorigenesis in many cancers, including prostate cancer (PCa). LncRNAs can regulate essential pathways that contribute to tumor initiation and progression with tissue specificity, which suggests that lncRNAs could be valuable biomarkers and therapeutic targets. Prostate cancer antigen 3 (PCA3), also known as differential display code 3 (DD3), is one such lncRNA that maps to chromosome 9q21-22. PCA3 expression is highly specific to PCa. In the present study, the level of PCA3 expression in prostate cancer cells was reduced by small interfering RNA (siRNA). Subsequently, the ability of LNCaP cell proliferation, invasion, and migration of PCa was compromised both in vivo and in vitro with the occurrence of cell autophagy. Recently, a novel regulatory mechanism has been proposed in which RNAs cross talk via competing with the shared microRNAs (miRNAs). In addition, lncRNAs can directly interact with RNA-binding proteins and then bind to the gene promoter region to further regulate gene expression. The proposed competitive endogenous RNAs mediate the bioavailability of miRNAs on their targets, thus imposing another level of post-transcriptional regulation. Here, we demonstrated that binding of Snail to the promoter region of PCA3 could activate the expression of PCA3. Down-regulation of PCA3 by silencing could increase the expression of the miRNA-1261, which then targeted at the PRKD3 gene (protein kinase D3) through competitive sponging. In summary, these results suggest that the transcription factor, Snail, activated the expression of lncRNA PCA3, which could inhibit the translation of PRKD3 protein via competitive miR-1261 sponging, and thus high expression of PRKD3 further promoted invasion and migration of prostate cancer.

A role for presenilin in post-stress regulation: effects of presenilin mutations on Ca2+ currents in Drosophila.

It has been shown that presenilin is involved in maintaining Ca2+ homeostasis in neurons, including regulating endoplasmic reticulum (ER) Ca2+ storage. From studies of primary cultures and cell lines, however, its role in stress-induced responses is still controversial. In the present study we analyzed the effects of presenilin mutations on membrane currents and synaptic functions in response to stress using an in vivo preparation. We examined voltage-gated K+ and Ca2+ currents at the Drosophila larval neuromuscular junction (NMJ) with voltage-clamp recordings. Our data showed that both currents were generally unaffected by loss-of-function or Alzheimer's disease (AD) -associated presenilin mutations under normal or stress conditions induced by heat shock (HS) or ER stress. In larvae expressing the mutant presenilins, prolonged Ca2+ tail current, reflecting slower deactivation kinetics of Ca2+ channels, was observed 1 day after stress treatments were terminated. It was further demonstrated that the L-type Ca2+ channel was specifically affected under these conditions. Moreover, synaptic plasticity at the NMJ was reduced in larvae expressing the mutant presenilins. At the behavioral level, memory in adult flies was impaired in the presenilin mutants 1 day after HS. The results show that presenilin function is important during the poststress period and its impairment contributes to memory dysfunction observed during adaptation to normal conditions after stress. Our findings suggest a new stress-related mechanism by which presenilin may be implicated in the neuropathology of AD.