APOE2 protects against Aß pathology by improving neuronal mitochondrial function through ERRα signaling.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disease and apolipoprotein E (APOE) genotypes (APOE2, APOE3, and APOE4) show different AD susceptibility. Previous studies indicated that individuals carrying the APOE2 allele reduce the risk of developing AD, which may be attributed to the potential neuroprotective role of APOE2. However, the mechanisms underlying the protective effects of APOE2 is still unclear. METHODS: We analyzed single-nucleus RNA sequencing and bulk RNA sequencing data of APOE2 and APOE3 carriers from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort. We validated the findings in SH-SY5Y cells and AD model mice by evaluating mitochondrial functions and cognitive behaviors respectively. RESULTS: The pathway analysis of six major cell types revealed a strong association between APOE2 and cellular stress and energy metabolism, particularly in excitatory and inhibitory neurons, which was found to be more pronounced in the presence of beta-amyloid (Aß). Moreover, APOE2 overexpression alleviates Aß1-42-induced mitochondrial dysfunction and reduces the generation of reactive oxygen species in SH-SY5Y cells. These protective effects may be due to ApoE2 interacting with estrogen-related receptor alpha (ERRα). ERRα overexpression by plasmids or activation by agonist was also found to show similar mitochondrial protective effects in Aß1-42-stimulated SH-SY5Y cells. Additionally, ERRα agonist treatment improve the cognitive performance of Aß injected mice in both Y maze and novel object recognition tests. ERRα agonist treatment increased PSD95 expression in the cortex of agonist-treated-AD mice. CONCLUSIONS: APOE2 appears to enhance neural mitochondrial function via the activation of ERRα signaling, which may be the protective effect of APOE2 to treat AD.

Analysis of Population Representation Among Willed Whole-Body Donors to Facilitate the Construction of a Body Donation Program in China: From the Perspective of Medical Students and Anatomists.

The body donation program of Peking Union Medical College was established in May 1999. From May 1999 to December 2017, a total of 5,576 registrants registered and 1,459 donors donated their bodies. Demographic and medical characteristics of the donors were analyzed. The top four causes of death were neoplasms, heart diseases, respiratory diseases, and cerebrovascular diseases. Age at death among donors who died of neoplasms were significantly lower than other causes of death (all p < .05), and the interval between registration and donation among donors who died of neoplasms was significantly shorter than that among donors with other causes (all p < .001). The age of donors when they registered (p < .001) and donated (p < .001) was significantly older than that of general Beijing population. This study may provide a guide for medical colleges or research institutions to establish or enhance their own body donation programs.

The top 100 most-cited articles citing human brain banking from 1970 to 2020: a bibliometric analysis.

Many articles involving human brain banks have been published. Bibliometric analysis can determine the history of the development of research and future research trends in a specific field. Three independent researchers retrieved and reviewed articles from the Web of Science database using the following strategy: "TS = (((brain OR cerebral) AND (bank* OR biobank*)) OR brainbank*)." The top 100 most-cited articles were identified and listed in descending order by total citations. Web of Science was used to identify ten recent articles describing bank construction. GeenMedical ( https://www.geenmedical.com/ ) was used to identify ten recent articles from journals with an impact factor (IF) > 20. The top 100 most-cited articles citing human brain banks were published between 1991 and 2017. Fifty-two percent of the articles focused on a specific type of neurodegenerative disease, and 16% discussed the construction and development of human brain banks. Articles using brain tissue had more total and annual citations than those on bank construction. Ten articles with high IFs were published from 2017 to 2019, and they were primarily studies using novel research techniques such RNA sequencing and genome-wide association studies. Most studies were published in journals specializing in neurology or neuroscience such as Movement Disorders (10%), and had been conducted in the United States (52%) by neurologists (62%). The top 100 most-cited articles and recent publications citing human brain banks and their bibliometric characteristics were identified and analyzed, which may serve as a useful reference and pave the way for further research.

Integrated bioinformatics analysis identifies shared immune changes between ischemic stroke and COVID 19.

Although COVID-19 is primarily a respiratory disease, its neurological complications, such as ischemic stroke (IS), have aroused growing concerns and reports. However, the molecular mechanisms that underlie IS and COVID-19 are not well understood. Therefore, we implemented transcriptomic analysis from eight GEO datasets consist of 1191 samples to detect common pathways and molecular biomarkers in IS and COVID-19 that help understand the linkage between them. Differentially expressed genes (DEGs) were detected for IS and COVID-19 separately for finding shared mechanisms and we found that immune-related pathways were outlined with statistical significance. JAK2, which was identified as a hub gene, was supposed to be a potential therapeutic gene targets during the immunological process of COVID-19 and IS. Besides, we found a decrease in the proportion of CD8+ T and T helper 2 cells in the peripheral circulation of both COVID and IS patients, and NCR3 expression was significantly correlated with this change. In conclusion, we demonstrated that transcriptomic analyses reported in this study could make a deeper understanding of the common mechanism and might be promising for effective therapeutic for IS and COVID-19.

Circular RNA as biomarkers for acute ischemic stroke: A systematic review and meta-analysis.

BACKGROUND: Rapid diagnosis of acute ischemic stroke (AIS) patients is still challenging, and reliable biomarkers are needed. Noncoding RNAs are important for many physiological activities, among which circular RNAs (circRNAs) have been proven to be more tissue-specific and conservative. Many recent studies found the potential of circRNAs as biomarkers for many diseases, including cardiovascular diseases, cancers, and ischemic stroke. This systemic review and meta-analysis aimed to identify circRNAs as potential biomarkers for AIS. METHODS: This study has been prospectively registered in PROSPERO (Registration No. 11 CRD42021288033). Published literature comparing circRNA expression profiles between AIS and non-AIS in human and animal models were retrieved from the articles published by January 2023 in major databases. We descriptively summarized the included studies, conducted meta-analysis under a random effects model, and did bioinformatics analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. RESULTS: Totally 23 studies were included, reporting 18 distinctive upregulated and 20 distinctive downregulated circRNAs. Diagnostic meta-analysis indicated discriminative ability of the circRNAs. Furthermore, circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1 were reported with the same regulation trend in more than one study (animal studies included). GO and KEGG enrichment analyses indicated that the target genes of these five circRNAs were enriched in regulating cell proliferation, apoptosis, and oxidative stress. CONCLUSIONS: This study demonstrates that circRNAs (circRNA HECTD1, circRNA DLGAP4, circRNA CDC14A, circRNA SCMH1, and circRNA TLK1) generally are promising as potential biomarkers for AIS. However, due to the limited number of studies, diagnostic value of individual circRNA could not be validated. More in vitro and in vivo functional studies are needed.

Transcriptomic analysis identifies shared biological foundations between ischemic stroke and Alzheimer's disease.

Aim: Alzheimer's disease (AD) and ischemic stroke (IS), two major neurological diseases, are suggested to be associated in clinical and pathophysiological levels. Previous studies have provided some insights into the possible genetic mechanisms behind the correlation between AD and IS, but this issue is still not clear. We implemented transcriptomic analysis to detect common hub genes and pathways to help promote the understanding of this issue. Materials and methods: Four gene expression profiling datasets (GSE16561, GSE58294, GSE63060, and GSE63061) of peripheral whole blood, which contain 108 IS samples, 284 AD samples, and 285 matched controls, were employed to detect differentially expressed genes (DEGs) for AD and IS, which were further analyzed for shared biological pathways, candidate drugs, and transcription factors. Protein-protein interaction (PPI) network and drug-target interaction analysis were applied to identify hub genes and drug targets, respectively. Result verification was done with other independent datasets (GSE37587, GSE46480, and GSE140829). The difference in proportions of various immune cells in the peripheral blood of AD and IS patients were evaluated using CIBERSORT. Results: We identified 74 DEGs and 18 biological processes with statistical significance shared by AD and IS, 9 of which were immune-related pathways. Five hub genes scored high in the topological analysis of the PPI network, and we also found eight drug target genes and candidate drugs which were associated with AD and IS. As for immunological changes, an increase in the proportion of M0 macrophages was found in the peripheral circulation of both AD and IS patients, and SOD1 expression was significantly correlated with this change. Conclusion: Collectively, the common DEGs and shared pathways found in this study suggest a potential shared etiology between AD and IS, behind which immune system, particularly the M0 macrophage elevation, might have important roles. While, the shared hub genes, potential therapeutic gene targets and drugs reported in this study provide promising treatment strategies for AD and IS.

Challenges of senior 8-year-program medical students' scientific research in China: A multicenter questionnaire-based study.

ABSTRACT: Among the diverse medical education systems in China, the 8-year program is dedicated to cultivating physician scientists. Although the research ability of senior students in 8-year medical programs is a pivotal quality, it remains unclear. This study aimed to clarify the current status and challenges of students' research experience, abilities, and outputs.A multicenter cross-sectional study was conducted in 5 medical schools in northern China. Electronic questionnaires were sent to 235 randomly chosen fifth-grade or sixth-grade 8-year-program medical students. A total of 211 responses were collected and analyzed using SPSS 22.0.Only 13.3% of participants chose research as their future career goal. Students generally felt that conducting research was stressful and difficult. The greatest obstacle was a lack of time due to heavy workloads. The 2 major motivations for research were graduation and/or future employment (75.8%) and research interest (24.2%). More than half of the students (142, 67.3%) had research experience by the time of the survey, among whom 84 students already had research outputs. A higher proportion of students with outputs was motivated by the requirements for graduation or employment compared to students without outputs (71.4% vs 55.2%, P  =  .046).Senior 8-year-program medical students in China generally had high pressure to conduct research and devoted their efforts to overcome these challenges. More guidance and novel encouragement to enhance students' initiative and interest in research could be provided by medical schools and educators in the future.

Investigating the Genetic Characteristics of Hippocampal Volume and Plasma ß-Amyloid in a Chinese Community-Dwelling Population.

BACKGROUND AND OBJECTIVES: The genetic characteristics and correlations of hippocampal volume and plasm Aß, probable endophenotypes for dementia, remain to be explored in Chinese community cohort. Using whole-exome sequencing and SNP-array genotyping, we sought to identify rare and common variants and genes influencing these two endophenotypes, and calculate their heritability and genetic correlation. METHODS: Association analyses with both whole-exome sequencing and SNP-array genotyping data were performed for hippocampal volumes and plasm Aß with mixed-effect linear regression model adjusted for sex, age, and total intracranial volume or APOE ε4 while considering familial relatedness. We also performed gene-level analysis for common and gene-burden analysis for rare variants. Heritability and genetic correlation were further examined. RESULTS: Totally 1,261 participants from a Chinese community cohort were included and we identified one gene, PTPRT, for hippocampal volume, with the top significant SNPs by whole genome-wide association study. rs6030076 (P=5.48×10-8, ß=-0.092, SE=0.017) from whole-exome sequencing and rs6030088 (P=8.24×10-9, ß=-105.22 SE=18.09) from SNP-array data, both located in this gene. Gene-burden analysis based on rare mutations detected 6 genes to be significantly associated with Aß. The SNP-based heritability was 0.43±0.13 for hippocampal volume and 0.2-0.3 for plasma Aß. The SNP-based genetic correlation between hippocampal volume and plasma Aß were negative. DISCUSSION: In this study, we identified several SNPs and one gene, PTPRT, which were not reported in previous GWASs, associated with hippocampal volume. Besides, the heritability and the genetic correlation gave an overview of hippocampal volume and plasma Aß. Our findings provide insights into the mechanisms behind the individual variances in these endophenotypes.

Analysis of Brain Donors' Demographic and Medical Characteristics to Facilitate the Construction of a Human Brain Bank in China.

The Chinese Academy of Medical Sciences and Peking Union Medical College (CAMS/PUMC) Human Brain Bank was established in December 2012 and had accomplished 197 brain donations by November 2017. The brain bank was based on a large-scale willed body donation program in CAMS/PUMC starting from 1999. Demographic and medical characteristic analysis of brain donors was conducted to facilitate the construction of the brain bank. The average postmortem delay of brain donors was 17.7 h and 77.7% of these donors died less than 15 km away from the brain bank. Donors were predominantly with higher-level education (p < 0.001) and at an older age when registration (p < 0.001) and donation (p < 0.001) occurred. Our results elucidated the characteristics of donors in the CAMS/PUMC Human Brain Bank, which may provide useful information to target potential donors and improve the quality and quantity of brain specimens. The current study may pave the way for the construction of a nationwide network of standardized human brain banks in China.