Interleukin-17 directly stimulates tumor infiltrating Tregs to prevent cancer development.

Background: Interleukin-17 (IL-17) family cytokines promote protective inflammation for pathogen resistance, but also facilitate autoimmunity and tumor development. A direct signal of IL-17 to regulatory T cells (Tregs) has not been reported and may help explain these dichotomous responses. Methods: We generated a conditional knockout of Il17ra in Tregs by crossing Foxp3-YFP-Cre mice to Il17ra-flox mice (Il17ra ΔTreg mice). Subsequently, we adoptively transferred bone marrow cells from Il17ra ΔTreg mice to a mouse model of sporadic colorectal cancer (Cdx2-Cre +/Apc F/+), to selectively ablate IL-17 direct signaling on Tregs in colorectal cancer. Single cell RNA sequencing and bulk RNA sequencing were performed on purified Tregs from mouse colorectal tumors, and compared to those of human tumor infiltrating Treg cells. Results: IL-17 Receptor A (IL-17RA) is expressed in Tregs that reside in mouse mesenteric lymph nodes and colon tumors. Ablation of IL-17RA, specifically in Tregs, resulted in increased Th17 cells, and exacerbated tumor development. Mechanistically, tumor-infiltrating Tregs exhibit a unique gene signature that is linked to their activation, maturation, and suppression function, and this signature is in part supported by the direct signaling of IL-17 to Tregs. To study pathways of Treg programming, we found that loss of IL-17RA in tumor Tregs resulted in reduced RNA splicing, and downregulation of several RNA binding proteins that are known to regulate alternative splicing and promote Treg function. Conclusion: IL-17 directly signals to Tregs and promotes their maturation and function. This signaling pathway constitutes a negative feedback loop that controls cancer-promoting inflammation in CRC.

Gut microbiota-mediated activation of GSDMD ignites colorectal tumorigenesis.

Activation of Gasdermin D (GSDMD) results in its cleavage, oligomerization, and subsequent formation of plasma membrane pores, leading to a form of inflammatory cell death denoted as pyroptosis. The roles of GSDMD in inflammation and immune responses to infection are well documented. However, whether GSDMD also plays a role in sporadic cancer development, especially that in the gut epithelium, remains unknown. Here, we show that GSDMD is activated in colorectal tumors of both human and mouse origins. Ablation of GSDMD in a mouse model of sporadic colorectal cancer resulted in reduced tumor formation in the colon and rectum, suggesting a tumor-promoting role of the protein in the gut. Both antibiotic-mediated depletion of gut microbiota and pharmacological inhibition of NLRP3 inflammasome reduced the activation of GSDMD. Loss of GSDMD resulted in reduced infiltration of immature myeloid cells, and increased numbers of macrophages in colorectal tumors. Activation of GSDMD is also accompanied by the aggregation of the endosomal sorting complex required for transport (ESCRT) membrane repair proteins on the membrane of colorectal tumor cells, suggesting that active membrane repairment may prevent pyroptosis induced by the formation of GSDMD pore in tumor cells. Our results show that gut microbiota/NLRP3-mediated activation of GSDMD promotes the development of colorectal tumors, and supports the use of NLRP3 inhibitors to treat colon cancer.

Cancer immunotherapy with enveloped self-amplifying mRNA CARG-2020 that modulates IL-12, IL-17 and PD-L1 pathways to prevent tumor recurrence.

Targeting multiple immune mechanisms may overcome therapy resistance and further improve cancer immunotherapy for humans. Here, we describe the application of virus-like vesicles (VLV) for delivery of three immunomodulators alone and in combination, as a promising approach for cancer immunotherapy. VLV vectors were designed to deliver single chain interleukin (IL)-12, short-hairpin RNA (shRNA) targeting programmed death ligand 1 (PD-L1), and a dominant-negative form of IL-17 receptor A (dn-IL17RA) as a single payload or as a combination payload. Intralesional delivery of the VLV vector expressing IL-12 alone, as well as the trivalent vector (designated CARG-2020) eradicated large established tumors. However, only CARG-2020 prevented tumor recurrence and provided long-term survival benefit to the tumor-bearing mice, indicating a benefit of the combined immunomodulation. The abscopal effects of CARG-2020 on the non-injected contralateral tumors, as well as protection from the tumor cell re-challenge, suggest immune-mediated mechanism of protection and establishment of immunological memory. Mechanistically, CARG-2020 potently activates Th1 immune mechanisms and inhibits expression of genes related to T cell exhaustion and cancer-promoting inflammation. The ability of CARG-2020 to prevent tumor recurrence and to provide survival benefit makes it a promising candidate for its development for human cancer immunotherapy.

The effect of an information intervention on the career commitment of medical students: evidence from a randomized experiment.

Introduction: The needs-based shortage of healthcare workers is severe worldwide and it would be exacerbated if many medical students switch to other careers after graduation. Maintaining and improving the career commitment of medical students, which could be a feasible, effective, and scalable way to reduce the attrition rate, is essential in medical education. We designed a randomized experiment to test whether an information intervention based on role modeling could enhance medical students' career commitment. Methods: In the randomized experiment, the sample (N = 36,482) was divided into the treatment group (N = 18,070) and the control group (N = 18,412). The intervention information consisted of image-text messages on Zhong Nanshan, who is an inspiring role model for he went to the frontline of COVID-19 in the most critical circumstances and received praise and affirmation from the public. Α difference-in-differences model was employed to identify the effect of the information intervention. Heterogeneous treatment effects were identified using sub-sample analyses. Results: The results showed that the information intervention statistically significantly reduced medical students' dropout intention by 2.7 percentage points (95% CI: -0.037 to -0.016, t = -4.95, p < 0.001), equivalent to 14.6% of the control group mean. This estimate indicates that the information intervention could significantly increase the career commitment of medical students. Finally, male and senior students were influenced more than their female and junior counterparts, which can be explained by their relatively high dropout intention. Conclusion: Role model-based information intervention improves the career commitment of medical students. The underlying behavioral model is that, when students use a role model as their reference point, they consider dropout as a substantial welfare loss. Role modeling is an effective way to improve the career commitment of medical students, especially for males and senior students.

How college-student academic undermatch affects students: Quasi-experimental evidence on multifaceted student outcomes.

Undermatching is a phenomenon in which students attend institutions that are less selective than the ones they could enroll given their academic credentials. Recent research suggests that undermatching may harm student development during college. However, there have been few comprehensive analyses of the causal relationship of undermatching and multifaceted college experience. Using college student longitudinal data from Beijing, China, we provide new quasi-experimental evidence on the effects of academic undermatch. This study extends the existing literature by focusing on a wide variety of student outcomes during college years, including learning motivation, behavior and academic performance, psychological attitudes and mental health, interpersonal relationships and involvement, and college satisfaction. Employing the exogenous admissions reform as the instrumental variable for undermatching, we find that undermatching predicts better academic performance and self-evaluation, but worse social relationships and college satisfaction. The results suggest that, although undermatched students are usually higher academic achievers than their college peers, they lack group identity and are not socially involved in college life.

Interleukin-17 Promotes the Infiltration of CD8+ T Cells into the Brain in a Mouse Model for Alzheimer's Disease.

BACKGROUND: Interleukin-17 (IL-17) family cytokines play critical roles in inflammation and pathogen resistance. Inflammation in the central nervous system, denoted as neuroinflammation, promotes the onset and progression of Alzheimer's disease (AD). Previous studies showed that IL-17A neutralizing antibody treatment alleviated Amyloid ß (Aß) burden in rodent models of AD, while overexpression of IL-17A in mouse lateral ventricles rescued part of the AD pathology. However, the involvement of IL-17 in AD and its mechanism of action remain largely unknown. METHODS: To investigate the role of IL-17 in AD, we crossed mice lacking the common receptor of IL-17 signaling (IL-17RA knockout mice) to the APP/PS1 mouse model of AD. We then analyzed the composition of immune cells and cytokines/chemokines during different phases of AD pathology, and interrogated the underlying mechanism by which IL-17 may regulate immune cell infiltration into AD brains. RESULTS: Ablation of IL-17RA in APP/PS1 mice decreased infiltration of CD8+ T cells and myeloid cells to mouse brain. IL-17 was able to promote the production of myeloid- and T cell-attracting chemokines CXCL1 and CXCL9/10 in primary glial cells. We also observed that IL-17 is upregulated in the late stage of AD development, and ectopic expression of IL-17 via adenoviral infection to the cortex trended towards worsened cognition in APP/PS1 mice, suggesting a pathogenic role of excessive IL-17 in AD. CONCLUSION: Our data show that IL-17 signaling promotes neuroinflammation in AD by accelerating the infiltration of CD8+ T lymphocytes and Gr1+ CD11b+ myeloid cells.

Global pathways: new evidence on the international graduate school choice of Chinese outbound students.

China serves as an indispensable recruitment market for higher education institutions across the globe. Using large-scale administrative and survey data from one of China's pipeline provinces for sending students abroad, we provide new evidence on the factors influencing Chinese students' graduate school choices internationally. We model international student mobility as a function of schooling-constrained, international migration, and consumption values. Descriptive results from nested logit model and multinomial logit model support the model predictions. We also construct counterfactual policy simulations by examining what would have happened under different potential scenarios in both China and destination countries. The simulation results show that the changes in Chinese college quality and family income are likely to affect the number of Chinese students studying abroad but not their distribution patterns among destination countries. In the meanwhile, factors including scholarship opportunities, work visa policies, and recruitment efforts in the destination countries would substantially shift Chinese students' choice of destination country and therefore the specific graduate school location. Supplementary Information: The online version contains supplementary material available at 10.1007/s10734-022-00979-6.

Prosocial modelling matters: the association between parent and faculty involvement in fighting COVID-19 with medical students' career commitment.

BACKGROUND: Role models are essential in medical education, yet empirical research is relatively insufficient on the influence of prosocial modelling on medical students' career commitment. The prosocial behaviour of medical staff involved in the fight against the novel coronavirus disease 2019 (COVID-19) at the beginning of 2020 presents an opportunity to fill the research gap. We explored and compared the different associations of the two most important role models for medical students - parents and faculty- with medical students' career commitment. METHODS: The cross-sectional study was conducted with 99,559 undergraduate students majoring in clinical medicine in mainland China. Questions were asked to collect information about participants in the battle against COVID-19, medical students' determination to practice medicine after graduation, as well as students' socio-demographic characteristics. Chi-square tests and hierarchical regressions were performed to examine the associations between parent and faculty involvement and students' career commitment. RESULTS: The results showed statistically significant associations between prosocial modelling during the COVID-19 pandemic in China and students' intention to pursue medical careers. The association of faculty involvement (OR = 1.165, p < .001) with students' career commitment was greater than that of parents (OR = 0.970, p > .05). For faculty involvement, the association was stronger among male students (OR = 1.323, p < .001) and students who were already determined to be doctors (OR = 1.219, p < .001) before the pandemic. CONCLUSIONS: Our study provides new evidence on the potential roles of parents and faculty in shaping medical students' career commitment. Encouraging faculty to act as positive role models could help medical students increase their intention to become doctors.KEY MESSAGESProsocial modelling could enhance students' intention to pursue medical careers.The association of prosocial behaviour of faculty is larger than that of parents on medical students.Those who have prior medical career commitment are much more likely to persist in the medical profession, and prosocial modelling of faculty is positively associated with their medical career commitment.

Still want to be a doctor? Medical student dropout in the era of COVID-19.

This research examines the intention of undergraduate medical students to withdraw from the medical profession and pursue a career in a different field upon graduation during COVID-19. We leverage the first and most comprehensive nationwide survey for medical education in China, which covered 98,668 enrolled undergraduate students from 90 out of 181 Chinese medical schools in 2020. We focus on these students' self-reported intention to leave the healthcare industry (the "dropout intention") before and after the outbreak of the epidemic. We also designed a randomized experiment to test whether and to what extent medical students dropout intention responded to an information nudge that highlighted the prosociality of health professionals in the fight against the virus. Results from a difference-in-differences model and a student fixed effect model suggest that after the onset of COVID-19, the proportion of Chinese undergraduate medical students with a dropout intention declined from 13.7% to 6.8%. Furthermore, the nudge information reduced the intent-to-drop-out probability by 0.8 additional percentage points for students in their early college years. There was large heterogeneity underneath the treatment effect. Specifically, we find that prior dropout intention and exposures to COVID-19-related information tended to mitigate the nudge effects. Data on students' actual dropout outcomes support our findings.

How do childhood abuse and neglect affect prosocial behavior? The mediating roles of different empathic components.

Background: Childhood abuse and neglect are typically considered as two different forms of maltreatment. Previous international studies have found differential effects of abuse and neglect on prosocial behavior, but this and the mediating pathway underlying these associations have not been examined in a Chinese sample. Our study aims to examine the effects of childhood abuse and neglect on prosocial behavior in Chinese participants and test the unique mediating roles of different empathic components in these associations. Methods: A total of 1,569 young adults (average age = 18.17 years) were recruited from a college that enrolls students from all provinces of China. Participants completed a series of questionnaires, including the Childhood Trauma Questionnaire, Interpersonal Reactivity Index, and Prosocial Tendencies Measure. Path analysis was conducted to determine the mediational relationships. Results: Emotional neglect had significant direct effect on prosocial behavior (ß = -0.108, p < 0.001), and could also impact prosocial behavior through the mediating roles of perspective-taking and empathic concern (effect size = -0.091 and -0.097 respectively, p < 0.001). Emotional abuse affected prosocial behavior only through personal distress (effect size = -0.072, p < 0.001). Physical abuse, sexual abuse and physical neglect have little effect on prosocial behavior and empathy. Conclusion: Childhood abuse and neglect have distinct influences on prosocial behavior. Emotional abuse and emotional neglect affect prosocial behavior through distinct pathways. This conclusion could help to establish precise interventions for improving prosocial behavior in maltreated individuals.

Students' initial perspectives on online learning experience in China during the COVID-19 outbreak: expanding online education for future doctors on a national scale.

BACKGROUND: During the early stage of COVID-19 outbreak in China, most medical undergraduate programs have to eventually embrace the maneuver of transferring to nearly 100% online-learning as a new routine for different curricula. And there is a lack of empirical evidence of effective medical education curriculum that has been completely implemented in an online format. This study summarizes medical students' perspectives regarding online-learning experience during the COVID-19 outbreak and presents reflection on medical education. METHODS: From February 21st to March 14th, 2020, the authors conducted survey of a nationally representative sample of undergraduate medical students from 90 medical schools in China. Participant demographics and responses were tabulated, and independent sample t-tests as well as multiple logistic regression models were used to assess the associations of demographic characteristics, prior online learning experience, and orientation with students' perspectives on the online learning experience. RESULTS: Among 118,030 medical students participated in the survey (response rate 52.4%), 99,559 provided valid data for the analysis. The sample is fairly nationally representative. 65.7% (65,389/99,559) supported great orientation and 62.1% (61,818/99,559) reported that they were satisfied with the ongoing online-learning experience. The most common problem students would encounter was the network congestion (76,277/99,559; 76.6%). Demographics, learning phases, and academic performance were associated with online-learning engagement and perceptions. Formal orientation and prior PU (perceived usefulness of online learning) were significantly positively associated with the satisfaction and evaluation of the online learning experience (p <  0.001). CONCLUSIONS: Data from this national survey indicates a relatively positive role of online learning as a formal teaching/learning approach in medical education. Considerations should be made regarding such application in aspects of students' different learning phases. We suggest that further policy interventions should be taken from technological, organizational, environmental, as well as individual aspects, to help improve the outcome of online learning for future doctors.

The elite exclusion: stratified access and production during the Chinese higher education expansion.

This paper presents new evidence on how enrollment expansion affects higher education access and production with a focus on social inequality and institutional stratification. From 1999 to 2012, the world's largest higher education expansion happened in China that annual college enrollment dramatically increased from 1,083,600 to 6,888,300. We evaluate this exogenous, unprecedented policy using nationally representative student-level survey data and newly available confidential institution-level data. Enrollment expansion, which reduced per-student resources, negatively impacted college quality as measured by value-added on graduates' employment and earnings. The inequality in access between high- and low-SES students and the stratified production between college institutional tiers persisted during expansion.

Whole-Transcriptome Analysis of APP/PS1 Mouse Brain and Identification of circRNA-miRNA-mRNA Networks to Investigate AD Pathogenesis.

Alzheimer's disease (AD) is one of the most common forms of dementia and is characterized by a progressive loss of cognition. A hallmark of AD is known to be the extensive distribution of neuronal tangles and amyloid plaques in the brain, but the molecular and cellular complexity of AD remains poorly elucidated, which limits the development of effective clinical treatments for AD. Accumulating evidence indicates that noncoding RNAs participate in AD-associated pathophysiology, but the details are largely unknown. Moreover, although recent studies have revealed a potential link between AD and circular RNA (circRNA)-associated competing endogenous RNA (ceRNA) networks, few genome-wide studies have identified putative circRNA-associated ceRNA pairs involved in AD. Here, we used deep RNA sequencing to systematically investigate circRNA-associated ceRNA mechanisms in the brain of AD model mice (APP/PS1). Our results identified 235, 30, and 1,202 significantly dysregulated circRNAs, microRNAs (miRNAs), and mRNAs, respectively, and we used the sequencing data to construct the most comprehensive circRNA-associated ceRNA networks to date in the APP/PS1 brain. Gene Ontology (GO) analysis revealed that the identified networks are involved in regulating AD development from distinct origins, such as from the dendrite (GO: 0030425) and the synapse (GO: 0045202). Following rigorous selection, the circRNA-associated ceRNA networks in this AD mouse model were discovered to be mainly involved in dendritic development and memory (Sorbs2) and mouse neural development (ALS2). This study presents the first systematic dissection of circRNA-associated ceRNA profiles in the APP/PS1 mouse brain, and the identified circRNA-associated ceRNA networks could provide insights that facilitate AD diagnosis and therapy in the future.

MiR-409-5p as a Regulator of Neurite Growth Is Down Regulated in APP/PS1 Murine Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. Recent studies suggest that miRNA expression changes are associated with the development of AD. Our previous study showed that the expression level of miR-409-5p was stably downregulated in the early stage of APP/PS1 double transgenic mice model of AD. We now report that miR-409-5p impairs neurite outgrowth, decreases neuronal viability, and accelerates the progression of Aß1 - 42-induced pathologies. In this study, we found that Aß1 - 42 peptide significantly decreased the expression of miR-409-5p, which was consistent with the expression profile of miR-409-5p in the APP/PS1 mice cortexes. Plek was confirmed to be a potential regulatory target of miR-409-5p by luciferase assay and Western blotting. Overexpression of miR-409-5p has an obvious neurotoxicity in neuronal cell viability and differentiation, whereas Plek overexpression could partially rescue neurite outgrowth from this toxicity. Some cytoskeleton regulatory proteins have been found to be related to AD pathogenesis. Our data show some clues that cytoskeletal reorganization may play roles in AD pathology. The early downregulation of miR-409-5p in AD progression might be a self-protective reaction to alleviate the synaptic damage induced by Aß, which may be used as a potential early biomarker of AD.

IL-17 inhibits CXCL9/10-mediated recruitment of CD8+ cytotoxic T cells and regulatory T cells to colorectal tumors.

BACKGROUND: The IL-17 family cytokines are potent drivers of colorectal cancer (CRC) development. We and others have shown that IL-17 mainly signals to tumor cells to promote CRC, but the underlying mechanism remains unclear. IL-17 also dampens Th1-armed anti-tumor immunity, in part by attracting myeloid cells to tumor. Whether IL-17 controls the activity of adaptive immune cells in a more direct manner, however, is unknown. METHODS: Using mouse models of sporadic or inducible colorectal cancers, we ablated IL-17RA in the whole body or specifically in colorectal tumor cells. We also performed adoptive bone marrow reconstitution to knockout CXCR3 in hematopoietic cells. Histological and immunological experimental methods were used to reveal the link among IL-17, chemokine production, and CRC development. RESULTS: Loss of IL-17 signaling in mouse CRC resulted in marked increase in the recruitment of CD8+ cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs), starting from early stage CRC lesions. This is accompanied by the increased expression of anti-inflammatory cytokines IL-10 and TGF-ß. IL-17 signaling also inhibits the production of T cell attracting chemokines CXCL9 and CXCL10 by tumor cells. Conversely, the inability of hematopoietic cells to respond to CXCL9/10 resulted in decreased tumor infiltration by CTLs and Tregs, decreased levels of IL-10 and TGF-ß, and increased numbers of tumor lesions. Blockade of IL-17 signaling resulted in increased expression of immune checkpoint markers. On the other hand, treatment of mouse CRC with anti-CTLA-4 antibody led to increased expression of pro-tumor IL-17. CONCLUSION: IL-17 signals to colorectal tumor cells and inhibits their production of CXCL9/10 chemokines. By doing so, IL-17 inhibits the infiltration of CD8+ CTLs and Tregs to CRC, thus promoting CRC development. Cancer immunotherapy may be benefited by the use of anti-IL-17 agents as adjuvant therapies, which serve to block both IL-17-mediated tumor promotion and T cell exclusion.

Pretreatment Inflammatory Indexes as Prognostic Predictors for Survival in Colorectal Cancer Patients Receiving Neoadjuvant Chemoradiotherapy.

This study was to evaluate the prognostic value of pretreatment inflammatory indexes including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) in colorectal cancer (CRC) patients receiving neoadjuvant chemoradiotherapy (CRT). We enrolled 98 eligible CRC patients and divided them into high or low NLR, PLR, LMR, and SII groups according to their median index value, respectively. Univariate and multivariate analysis were performed to identify the potential predictors of progression-free survival (PFS) and overall survival (OS). In the univariate analysis, ECOG performance status, distant metastasis, NLR, PLR, LMR, and SII were found to be significantly associated with PFS and OS. In the multivariate analysis, ECOG performance status, distant metastasis, and NLR were identified to be independent predictors of PFS (HR 2.487, p = 0.012; HR 2.422, p = 0.042; HR 2.243, p = 0.034, respectively), and OS (HR 2.237, p = 0.018; HR 2.757, p = 0.020; HR 2.336, p = 0.017, respectively). The results of our study revealed that ECOG performance status, distant metastasis and NLR were independent prognostic factors of PFS and OS in CRC patients receiving neoadjuvant CRT.

Pre-treatment inflammatory indexes as predictors of survival and cetuximab efficacy in metastatic colorectal cancer patients with wild-type RAS.

This study aims at evaluating the prognostic significance of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation indexes (SII) in metastatic colorectal cancer (mCRC) patients treated with cetuximab. Ninety-five patients receiving cetuximab for mCRC were categorized into the high or low NLR, PLR, LMR, and SII groups based on their median index values. Univariate and multivariate survival analysis were performed to identify the indexes' correlation with progression-free survival (PFS) and overall survival (OS). In the univariate analysis, ECOG performance status, neutrphil counts, lymphocyte counts, monocyte counts, NLR, PLR, and LDH were associated with survival. Multivariate analysis showed that ECOG performance status of 0 (hazard ratio [HR] 3.608, p < 0.001; HR 5.030, p < 0.001, respectively), high absolute neutrophil counts (HR 2.837, p < 0.001; HR 1.922, p = 0.026, respectively), low lymphocyte counts (HR 0.352, p < 0.001; HR 0.440, p = 0.001, respectively), elevated NLR (HR 3.837, p < 0.001; HR 2.467, p = 0.006) were independent predictors of shorter PFS and OS. In conclusion, pre-treatment inflammatory indexes, especially NLR were potential biomarkers to predict the survival of mCRC patients with cetuximab therapy.

Rpph1 Upregulates CDC42 Expression and Promotes Hippocampal Neuron Dendritic Spine Formation by Competing with miR-330-5p.

Alzheimer's disease (AD) is a heterogeneous neurodegenerative disease. Recent studies employing microRNA-seq and genome-wide sequencing have identified some non-coding RNAs that are influentially involved in AD pathogenesis. Non-coding RNAs can compete with other endogenous RNAs by microRNA response elements (MREs) and manipulate biological processes, such as tumorigenesis. However, only a few non-coding RNAs have been reported in the pathogenesis of AD. In this study, we constructed the first competing endogenous RNA (ceRNA) network leveraging whole transcriptome sequencing and a previously studied microRNA-seq of APPswe/PS1ΔE9 transgenic mice. The underlying mechanisms for the involvement of ceRNA in AD were validated using the Dual Luciferase Reporter Assay, detection of transcription levels by quantitative RT-PCR and translation levels by Western blotting, and morphological examination in primary cultured neurons. In the ceRNA network, four lncRNAs (C030034L19Rik, Rpph1, A830012C17Rik, and Gm15477) and five miRNAs (miR-182-5p, miR-330-5p, miR-326-3p, miR-132-3p, and miR-484) are enriched in nine pathways and an AD-related gene pool. Among them, Ribonuclease P RNA component H1 (Rpph1) is upregulated in the cortex of APPswe/PS1ΔE9 mice compared to wild type controls. Rpph1 binds to miR326-3p/miR-330-5p and causes the release of their downstream target Cdc42, which leads to CDC42 upregulation. This effect was disrupted upon mutation of the MRE on Rpph1. Moreover, overexpression of Rpph1 increased dendritic spine density in primary cultured hippocampal pyramidal neurons, whereas knocking down of Rpph1 had the reverse effect. In conclusion, Rpph1 modulates CDC42 expression level in a ceRNA-dependent manner, which may represent a compensatory mechanism in the early stage of the AD pathogenesis.

The Protective Role of microRNA-200c in Alzheimer's Disease Pathologies Is Induced by Beta Amyloid-Triggered Endoplasmic Reticulum Stress.

MicroRNAs are small non-coding RNAs that repress the expression of their target proteins. The roles of microRNAs in the development of Alzheimer's disease (AD) are not clear. In this study we show that miR-200c represses the expression of PTEN protein. PTEN downregulation by miR-200c supports the survival and differentiation of cultured neurons. AD is a progressive neurodegenerative disease signified by beta amyloid (Aß) peptide aggregation and deposition. In a mouse model of AD that is induced by APPswe and PS1ΔE9 double transgenes, we found Aß deposition results in neuronal ER stress that induces miR200c. Pharmacological blockade of ER stress inhibited Aß-induced miR-200c overexpression in AD brains. MiR-200c was detected in the serum of both AD mice and human AD patients. These findings suggest that miR-200c functions as part of the neuronal cell-intrinsic adaptive machinery, and supports neuronal survival and differentiation in response to Aß induced ER-stress by downregulating PTEN.

Role of miR-211 in Neuronal Differentiation and Viability: Implications to Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is an age-related irreversible neurodegenerative disorder characterized by extracellular ß Amyloid(Aß) deposition, intracellular neurofibrillary tangles and neuronal loss. The dysfunction of neurogenesis and increased degeneration of neurons contribute to the pathogenesis of AD. We now report that miR-211-5p, a small non-coding RNA, can impair neurite differentiation by directly targeting NUAK1, decrease neuronal viability and accelerate the progression of Aß-induced pathologies. In this study, we observed that during embryonic development, the expression levels of miR-211-5p were down-regulated in the normal cerebral cortexes of mice. However, in APPswe/PS1ΔE9 double transgenic adult mice, it was up-regulated from 9 months of age compared to that of the age-matched wild type mice. Studies in primary cortical neuron cultures demonstrated that miR-211-5p can inhibit neurite growth and branching via NUAK1 repression and decrease mature neuron viability. The impairments were more obvious under the action of Aß. Our data showed that miR-211-5p could inhibit cortical neuron differentiation and survival, which may contribute to the synaptic failure, neuronal loss and cognitive dysfunction in AD.