Genetic characterization of the ALFA study: Uncovering genetic profiles in the Alzheimer's continuum.

INTRODUCTION: In 2013, the ALzheimer's and FAmilies (ALFA) project was established to investigate pathophysiological changes in preclinical Alzheimer's disease (AD), and to foster research on early detection and preventive interventions. METHODS: We conducted a comprehensive genetic characterization of ALFA participants with respect to neurodegenerative/cerebrovascular diseases, AD biomarkers, brain endophenotypes, risk factors and aging biomarkers. We placed particular emphasis on amyloid/tau status and assessed gender differences. Multiple polygenic risk scores were computed to capture different aspects of genetic predisposition. We additionally compared AD risk in ALFA to that across the full disease spectrum from the Alzheimer's Disease Neuroimaging Initiative (ADNI). RESULTS: Results show that the ALFA project has been successful at establishing a cohort of cognitively unimpaired individuals at high genetic predisposition of AD. DISCUSSION: It is, therefore, well-suited to study early pathophysiological changes in the preclinical AD continuum. Highlights Prevalence of ε4 carriers in ALzheimer and FAmilies (ALFA) is higher than in the general European population The ALFA study is highly enriched in Alzheimer's disease (AD) genetic risk factors beyond APOE AD genetic profiles in ALFA are similar to clinical groups along the continuum ALFA has succeeded in establishing a cohort of cognitively unimpaired individuals at high genetic AD risk ALFA is well suited to study pathogenic events/early pathophysiological changes in AD.

Brain transcriptomic profiling reveals common alterations across neurodegenerative and psychiatric disorders.

Neurodegenerative and neuropsychiatric disorders (ND-NPs) are multifactorial, polygenic and complex behavioral phenotypes caused by brain abnormalities. Large-scale collaborative efforts have tried to identify the genetic architecture of these conditions. However, the specific and shared underlying molecular pathobiology of brain illnesses is not clear. Here, we examine transcriptome-wide characterization of eight conditions, using a total of 2,633 post-mortem brain samples from patients with Alzheimer's disease (AD), Parkinson's disease (PD), Progressive Supranuclear Palsy (PSP), Pathological Aging (PA), Autism Spectrum Disorder (ASD), Schizophrenia (Scz), Major Depressive Disorder (MDD), and Bipolar Disorder (BP)-in comparison with 2,078 brain samples from matched control subjects. Similar transcriptome alterations were observed between NDs and NPs with the top correlations obtained between Scz-BP, ASD-PD, AD-PD, and Scz-ASD. Region-specific comparisons also revealed shared transcriptome alterations in frontal and temporal lobes across NPs and NDs. Co-expression network analysis identified coordinated dysregulations of cell-type-specific modules across NDs and NPs. This study provides a transcriptomic framework to understand the molecular alterations of NPs and NDs through their shared- and specific gene expression in the brain.

Single-cell Transcriptional Changes in Neurodegenerative Diseases.

In recent decades, our understanding of the molecular changes involved in neurodegenerative diseases has been transformed. Single-cell RNA sequencing and single-nucleus RNA sequencing technologies have been applied to provide cellular and molecular details of the brain at the single-cell level. This has expanded our knowledge of the central nervous system and provided insights into the molecular vulnerability of brain cell types and underlying mechanisms in neurodegenerative diseases. In this review, we highlight the recent advances and findings related to neurodegenerative diseases using these cutting-edge technologies.

DNA methylation signature as a biomarker of major neuropsychiatric disorders.

DNA methylation is a broadly-investigated epigenetic modification that has been considered as a heritable and reversible change. Previous findings have indicated that DNA methylation regulates gene expression in the central nervous system (CNS). Also, disturbance of DNA methylation patterns has been associated with destructive consequences that lead to human brain diseases such as neuropsychiatric disorders (NPDs). In this review, we comprehensively discuss the mechanism and function of DNA methylation and its most recent associations with the pathology of NPDs-including major depressive disorder (MDD), schizophrenia (SZ), autism spectrum disorder (ASD), bipolar disorder (BD), and attention/deficit hyperactivity disorder (ADHD). We also discuss how heterogeneous findings demand further investigations. Finally, based on the recent studies we conclude that DNA methylation status may have implications in clinical diagnostics and therapeutics as a potential epigenetic biomarker of NPDs.

Transposable elements in brain health and disease.

Transposable elements (TEs) occupy a large fraction of the human genome but only a small proportion of these elements are still active today. Recent works have suggested that TEs are expressed and active in the brain, challenging the dogma that neuronal genomes are static and revealing that they are susceptible to somatic genomic alterations. These new findings have major implications for understanding the neuroplasticity of the brain, which could hypothetically have a role in behavior and cognition, and contribute to vulnerability to disease. As active TEs could induce genetic diversity and mutagenesis, their influences on human brain development and diseases are of great interest. In this review, we will focus on the active TEs in the human genome and discuss in detail their impacts on human brain development. Furthermore, the association between TEs and brain-related diseases is discussed.

Changes in mean platelet volume and hematologic indices in patients with panic disorder due to oxidative stress.

OBJECTIVE: Cardiovascular disorders are common in patients with panic disorder (PD), usually mediated by platelets. The present study was conducted to evaluate oxidative stress conditions and complete analysis of blood cells in patients with PD. SETTING AND SAMPLE POPULATION: Sixty healthy individuals and 60 patients were included in the study. Whole blood and serum samples were obtained from patients and controls. MATERIALS & METHOD: Hematological studies, including blood cells count, hemoglobin, and hematocrit, were carried out on whole blood samples. In addition, oxidative stress indices including total antioxidant capacity, free oxygen species, and malondialdehyde concentration were measured in serum samples. RESULTS: Results showed that patients with PD had a significant increase in mean platelet volume index (MPV), platelet distribution width (PDW), red blood cell distribution width (RDW), and mean corpuscular hemoglobin concentration (MCHC) compared with healthy subjects (p < .05). Also, oxidative stress indices were significantly elevated in patients with PD compared with control group (p < .05). CONCLUSION: Elevated MPV is a hematologic indicator for patients with PD. This disorder may be caused by impaired serotonin metabolism, resulting in increased oxidative stress, as well as in platelet serotonin transporters. Regarding elevated oxidative stress, the risk of cardiovascular complications is high in patients with PD.

The role and function of long non-coding RNAs in osteoarthritis.

Osteoarthiritis (OA) is the most prevalent disease of articulating joints in human that frequently results in joint pain, movement limitations, inflammation, and progressive degradation of articular cartilage. The etiology of OA is not completely clear and there is no full treatment for this disease. Molecular investigations have revealed the involvement of non-coding RNAs such as Long non-coding RNAs (lncRNAs) in OA pathogenesis. LncRNAs play roles in multiple cellular and biological processes. Moreover, numerous lncRNAs are differentially expressed in human OA cartilage. In this review, we underlie the increasing evidence for the critical role of lncRNAs in OA pathogenesis reviewing the latest researches.

The importance of long non-coding RNAs in neuropsychiatric disorders.

In the last decade, transcriptome analyses have discovered thousands of long non-coding RNAs (lncRNAs) which are assumed as a fundamental part of the gene regulatory networks in the cell. Intriguingly, lncRNAs are abundantly enriched in the brain, displaying elaborate spatiotemporal expression profiles and modulation. They diversely participate in the delicate regulation of the central nervous system (CNS) development including self-renewal maintenance, cell fate decision, synapse plasticity, synaptogenesis and memory formation. Moreover, lncRNAs have vastly demonstrated correlations with mental illnesses such as neuropsychiatric disorders (NPDs), implying the vital jobs of these yet poorly-understood transcripts. Here, we underlie the accumulating evidence for the significance of lncRNAs in neural networks and their impairment in several NPDs including autism spectrum disorder (ASD), schizophrenia (SZ), intellectual disability (ID), major depressive disorder (MDD), Rett syndrome (RTT) and others.

Profiling of miRNAs in serum of children with attention-deficit hyperactivity disorder shows significant alterations.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD), a common psychiatric disorder, is identified by abnormal levels of impulsivity, inattention, and hyperactivity. MiRNAs play important roles in neural network development of the brain. Circulating miRNAs (cmiRNAs) are offered as promising noninvasive markers for psychiatric disorders. In this study, the expression level of neurologically relevant miRNAs was evaluated in serum samples of ADHD individuals. METHODS: RNA extraction was performed for 60 subjects with ADHD and 60 healthy controls, and the cDNAs were synthesized for all the miRNAs. The expression level of 84 cmiRNAs was then examined in 4 ADHD subjects and 4 controls. The altered expression of 10 cmiRNAs was further evaluated in validation cohort comprising 56 ADHD and 56 control samples by qPCR. The diagnostic power of the miRNAs was determined by use of Receiver-operating characteristic (ROC) analysis. The cmiRNAs target genes were predicted using DIANA mirPath software and gene ontology enrichment analysis was performed using Cytoscape CLUGO. RESULTS: Initially, 10 miRNAs showed differential expression in ADHD individuals. Further analysis confirmed four miRNAs (hsa-miR-101-3p, hsa-miR-130a-3p, hsa-miR-138-5p and hsa-miR-195-5p) upregulated and one miRNA (hsa-miR-106b-5p) downregulated. These miRNAs showed significant predictive values for discriminating ADHD individuals. Enrichment analysis highlighted the involvement of the deregulated cmiRNAs in many canonical neurobiological pathways and mechanisms. CONCLUSIONS: Our report is the first comprehensive study on the expression profiling of miRNAs in serum of ADHD subjects. These findings suggest a set of cmiRNAs as potential noninvasive biomarkers for ADHD.

Increased BACE1-AS long noncoding RNA and ß-amyloid levels in heart failure.

AIMS: Antisense long noncoding RNAs (ncRNAs) are transcripts emerging from the opposite strand of a coding-RNA region and their role in heart failure (HF) is largely unknown. Additionally, HF and Alzheimer's disease (AD) share several non-genetic effectors and risk factors. We investigated the regulation of the ß-secretase-1 (BACE1) gene and of its antisense transcript BACE1-AS in ischaemic HF. METHODS AND RESULTS: BACE1 and BACE1-AS expression was measured in left ventricle biopsies from 18 patients affected by non-end stage ischaemic HF and 17 matched controls. The levels of both transcripts were increased in HF patients. Likewise, both transcripts increased also in a mouse model of ischaemic HF, and their expression was directly correlated. BACE1-AS was expressed by all cardiac cell types and BACE1-AS up- or down-modulation in cultured cardiomyocytes and endothelial cells induced a concordant regulation of the cognate BACE1 transcript. Interestingly, BACE1 increase also induced the intracellular accumulation of its product ß-amyloid. In keeping with these findings, higher BACE1 protein and ß-amyloid peptide levels were also observed in HF. Moreover, increased ß-amyloid 1-40 was also found in the plasma of HF patients. Transcriptomic changes of BACE1-AS overexpressing and ß-amyloid 1-40 treated cells were largely overlapping and indicated changes of relevant biological process such as 'cell cycle and proliferation', 'apoptosis', and 'DNA repair' as well as 'TGFß-, TNFα-, p38-, EGFR-signalling', suggesting a potential maladaptive role of the BACE1-AS/BACE1/ß-amyloid axis. Accordingly, the administration of ß-amyloid peptides decreased the cell viability in endothelial cells and in both human IPS-derived and mouse cardiomyocytes. Moreover, both ß-amyloid treatment and BACE1-AS overexpression increased endothelial cell apoptosis, and this effect was prevented by BACE1 silencing. CONCLUSION: Given the neurotoxic role of ß-amyloid in AD, dysregulation of the BACE1/BACE1-AS/ß-amyloid axis might be relevant in HF pathogenesis, further implicating ncRNAs in the complex scenario of proteotoxicity in cardiac dysfunction.

Tissue Specific Expression Levels of Apoptosis Involved Genes Have Correlations with Codon and Amino Acid Usage.

Different mechanisms, including transcriptional and post transcriptional processes, regulate tissue specific expression of genes. In this study, we report differences in gene/protein compositional features between apoptosis involved genes selectively expressed in human tissues. We found some correlations between codon/amino acid usage and tissue specific expression level of genes. The findings can be significant for understanding the translational selection on these features. The selection may play an important role in the differentiation of human tissues and can be considered for future studies in diagnosis of some diseases such as cancer.

6-Methoxy Podophyllotoxin Induces Apoptosis via Inhibition of TUBB3 and TOPIIA Gene Expressions in 5637 and K562 Cancer Cell Lines.

OBJECTIVE: Podophyllotoxin (PTOX), a natural compound in numerous plants, contains remarkable biological properties that include anti-tumor, anti-viral such as anti-human im- munodeficiency virus (HIV) activities. In order to avoid its adverse effects, various com- pounds have been derived from PTOX. 6-methoxy PTOX (MPTOX) is one of the natural PTOX derivatives with an extra methoxy group. MPTOX is mostly isolated from the Linum species. This study has sought to determine the biological effects of MPTOX on cancer cell lines, 5637 and K562. MATERIALS AND METHODS: In this experimental study, we treated the 5637 and K562 cancer cell lines with MPTOX in a doseand time-dependent manner. Apoptosis was examined by flow cytometry and viability rate was analyzed by the MTT assay. Expressions of the tubulin (TUBB3) and topoisomerase II (TOPIIA) genes were determined by real-time poly- merase chain reaction (PCR). RESULTS: Treatment with MPTOX led to significant induction of apoptosis in cancer cells compared to control cells. Gene expression analysis showed reduced levels of TUBB3 and TOPIIA mRNA following MPTOX treatment. CONCLUSION: MPTOX inhibited TUBB3 and TOPIIA gene expression and subsequently induced cell death through apoptosis. These results suggested that MPTOX could be considered a potential anti-tumor agent.

In vitro Cytotoxic and Antimicrobial Activity of Essential Oil From Satureja Intermedia.

BACKGROUND: Many members of the genus Satureja have aromatic and medicinal characteristics. Objectives. OBJECTIVES: The purpose of the present work was to determine cytotoxic activity of the essential oil of S. intermedia CA Mey (Lamiaceae) on two human cancerous cell lines and its in vitro inhibitory effects against 11 pathogenic bacteria and fungi as well. MATERIALS AND METHODS: The essential oil was isolated by hydrodistillation and analyzed by combination of capillary GC-FID and GC-MS. The in vitro toxicological study was based on the MTT cytotoxicity assay and antimicrobial activity of the essential oil was studied according to the disc diffusion method and MIC value. RESULTS: Thymol (34.5%), γ-terpinene (18.2%) and ρ-cymene (10.5%) were the main components of the essential oil. The toxicological study on 5637 and KYSE cell lines showed IC50 values of 156 µg/ml. The essential oil exhibited considerable antimicrobial activity on tested bacteria and fungi. CONCLUSIONS: From the results of the present study, it may be concluded that the essential oil of S. intermedia and its major constitutes are interesting in antibacterial and anticancer applications.