Presenilin-1-Derived Circular RNAs: Neglected Epigenetic Regulators with Various Functions in Alzheimer's Disease.

The presenilin-1 (PSEN1) gene is crucial in developing Alzheimer's disease (AD), a progressive neurodegenerative disorder and the most common cause of dementia. Circular RNAs (circRNAs) are non-coding RNA generated through back-splicing, resulting in a covalently closed circular molecule. This study aimed to investigate PSEN1-gene-derived circular RNAs (circPSEN1s) and their potential functions in AD. Our in silico analysis indicated that circPSEN1s (hsa_circ_0008521 and chr14:73614502-73614802) act as sponge molecules for eight specific microRNAs. Surprisingly, two of these miRNAs (has-mir-4668-5p and has-mir-5584-5p) exclusively interact with circPSEN1s rather than mRNA-PSEN1. Furthermore, the analysis of pathways revealed that these two miRNAs predominantly target mRNAs associated with the PI3K-Akt signaling pathway. With sponging these microRNAs, circPSEN1s were found to protect mRNAs commonly targeted by these miRNAs, including QSER1, BACE2, RNF157, PTMA, and GJD3. Furthermore, the miRNAs sequestered by circPSEN1s have a notable preference for targeting the TGF-ß and Hippo signaling pathways. We also demonstrated that circPSEN1s potentially interact with FOXA1, ESR1, HNF1B, BRD4, GATA4, EP300, CBX3, PRDM9, and PPARG proteins. These proteins have a prominent preference for targeting the TGF-ß and Notch signaling pathways, where EP300 and FOXA1 have the highest number of protein interactions. Molecular docking analysis also confirms the interaction of these hub proteins and Aß42 with circPSEN1s. Interestingly, circPSEN1s-targeted molecules (miRNAs and proteins) impacted TGF-ß, which served as a shared signaling pathway. Finally, the analysis of microarray data unveiled distinct expression patterns of genes influenced by circPSEN1s (WTIP, TGIF, SMAD4, PPP1CB, and BMPR1A) in the brains of AD patients. In summary, our findings suggested that the interaction of circPSEN1s with microRNAs and proteins could affect the fate of specific mRNAs, interrupt the function of unique proteins, and influence cell signaling pathways, generally TGF-ß. Further research is necessary to validate these findings and gain a deeper understanding of the precise mechanisms and significance of circPSEN1s in the context of AD.

TNF-α/STAT1/CXCL10 mutual inflammatory axis that contributes to the pathogenesis of experimental models of multiple sclerosis: A promising signaling pathway for targeted therapies.

BACKGROUND: Identifying mutual neuroinflammatory axis in different experimental models of multiple sclerosis (MS) is essential to evaluate the de- and re-myelination processes and improve therapeutic interventions' reproducibility. METHODS: The expression profile data set of EAE (GSE47900) and cuprizone (GSE100663) models were downloaded from the Gene Expression Omnibus database. The R package and GEO2R software processed these raw chip data. Gene Ontology (GO) functional analysis, KEGG pathway analysis, and protein-protein interaction network analysis were performed to investigate interactions between common differentially expressed genes (DEGs) in all models. Finally, the ELISA method assessed the protein level of highlighted mutual cytokines in serum. RESULTS: Our data introduced 59 upregulated [CXCL10, CCL12, and GBP6 as most important] and 17 downregulated [Serpinb1a, Prr18, and Ugt8a as most important] mutual genes. The signal transducer and activator of transcription 1 (STAT1) and CXCL10 were the most crucial hub proteins among mutual upregulated genes. These mutual genes were found to be mainly involved in the TNF-α, TLRs, and complement cascade signaling, and animal models shared 26 mutual genes with MS individuals. Finally, significant upregulation of serum level of TNF-α/IL-1ß/CXCL10 cytokines was confirmed in all models in a relatively similar pattern. CONCLUSION: For the first time, our study revealed the common neuroinflammatory pathway in animal models of MS and introduced candidate hub genes for better evaluating the preclinical efficacy of pharmacological interventions and designing prospective targeted therapies.

The interplay between tauopathy and aging through interruption of UPR/Nrf2/autophagy crosstalk in the Alzheimer's disease transgenic experimental models.

PURPOSE: Alzheimer's disease (AD) is the most common form of tauopathy that usually occursduring aging and unfolded protein response (UPR), oxidative stress and autophagy play a crucialrole in tauopathy-induced neurotoxicity. The aim of this study was to investigate the effects oftauopathy on normal brain aging in a Drosophila model of AD. METHOD: We investigated the interplay between aging (10, 20, 30, and 40 days) and human tauR406W (htau)-induced cell stress in transgenic fruit flies. RESULTS: Tauopathy caused significant defects in eye morphology, a decrease in motor function and olfactory memory performance (after 20 days), and an increase in ethanol sensitivity (after 30 days). Our results showed a significant increase in UPR (GRP78 and ATF4), redox signalling (p-Nrf2, total GSH, total SH, lipid peroxidation, and antioxidant activity), and regulatory associated protein of mTOR complex 1 (p-Raptor) activity in the control group after 40 days, while the tauopathy model flies showed an advanced increase in the above markers at 20 days of age. Interestingly, only the control flies showed reduced autophagy by a significant decrease in the autophagosome formation protein (dATG1)/p-Raptor ratio at 40 days of age. Our results were also confirmed by bioinformatic analysis of microarray data from tauPS19 transgenic mice (3, 6, 9, and 12 months), in which tauopathy increased expression of heme oxygenase 1, and glutamate-cysteine ligase catalytic subunit and promote aging in transgenic animals. CONCLUSIONS: Overall, we suggest that the neuropathological effects of tau aggregates may be accelerated brain aging, where redox signaling and autophagy efficacy play an important role.

MAPK Is a Mutual Pathway Targeted by Anxiety-Related miRNAs, and E2F5 Is a Putative Target for Anxiolytic miRNAs.

Anxiety-related disorders (ARDs) are chronic neuropsychological diseases and the sixth leading cause of disability in the world. As dysregulation of microRNAs (miRs) are observed in the pathological course of neuropsychiatric disorders, the present study aimed to introduce miRs that underlie anxiety processing in the brain. First, we collected the experimentally confirmed anxiety-related miRNAs (ARmiRs), predicted their target transcripts, and introduced critical cellular pathways with key commune hub genes. As a result, we have found nine anxiolytic and ten anxiogenic ARmiRs. The anxiolytic miRs frequently target the mRNA of Acyl-CoA synthetase long-chain family member 4 (Acsl4), AFF4-AF4/FMR2 family member 4 (Aff4), and Krüppel like transcription factor 4 (Klf4) genes, where miR-34b-5p and miR-34c-5p interact with all of them. Moreover, the anxiogenic miRs frequently target the mRNA of nine genes; among them, only two miR (miR-142-5p and miR-218-5p) have no interaction with the mRNA of trinucleotide repeat-containing adaptor 6B (Tnrc6b), and miR-124-3p interacts with all of them where MAPK is the main signaling pathway affected by both anxiolytic and anxiogenic miR. In addition, the anxiolytic miR commonly target E2F transcription factor 5 (E2F5) in the TGF-ß signaling pathway, and the anxiogenic miR commonly target Ataxin 1 (Atxn1), WASP-like actin nucleation promoting factor (Wasl), and Solute Carrier Family 17 Member 6 (Slc17a6) genes in the notch signaling, adherence junction, and synaptic vesicle cycle pathways, respectively. Taken together, we conclude that the most important anxiolytic (miR-34c, Let-7d, and miR-17) and anxiogenic (miR-19b, miR-92a, and 218) miR, as hub epigenetic modulators, potentially influence the pathophysiology of anxiety, primarily via interaction with the MAPK signaling pathway. Moreover, the role of E2F5 as a novel putative target for anxiolytic miRNAs in ARDs disorders deserves further exploration.

Neuroprotective effect of the Nrf2/ARE/miRNA145-5p signaling pathway in the early phase of spinal cord injury.

AIMS: Spinal cord injury (SCI) is a debilitating neurological condition often associated with chronic neuroinflammation and redox imbalance. Oxidative stress is one of the main hallmark of secondary injury of SCI which is tightly regulated by nuclear factor E2-related factor 2/antioxidant response element (Nrf2/ARE) signaling. In this study, we aimed at investigating the interplay between inflammation-related miRNAs and the Nrf2 pathway in animal model of SCI. MATERIALS AND METHODS: The expression of selected four validated miRNA-target pairs (miRNA223-3p, miRNA155-5p, miRNA145-5p, and miRNA124-3p) was examined at different time points (6 h, 12 h, 1 day, 3 day and 7 day) after SCI. Further, using GFAP-specific kelch-like ECH-associated protein 1 deletion (Keap1-/-) and whole-body Nrf2-/- knockout mice, we investigated the potential interplay between each miRNA and the Keap1/Nrf2 signaling system. KEY FINDINGS: The expression of all miRNAs except miRNA155-5p significantly increased 24 h after SCI and decreased after 7 days. Interestingly, Keap1-/- mice only showed significant increase in the miRNA145-5p after 24 h SCI compared to the WT group. In addition, Keap1-/- mice showed significant decrease in CXCL10/12 (CXCL12 increased in Nrf2-/- mice), and TNF-α, and an increase in Mn-SOD and NQO-1 (Mn-SOD and NQO-1 decreased in Nrf2-/- mice) compared to WT mice. SIGNIFICANCE: Our results suggest that astrocytic hyperactivation of Nrf2 exert neuroprotective effects at least in part through the upregulation of miRNA145-5p, a negative regulator of astrocyte proliferation, and induction of ARE in early phase of SCI. Further studies are needed to investigate the potential interplay between Nrf2 and miRNA145-5p in neuroinflammatory condition.

Recent Updates in the Alzheimer's Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials.

BACKGROUND: Alzheimer's disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. OBJECTIVE: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. METHODS: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were "Alzheimer's disease" or "dementia" and "medicine" or "drug" or "treatment" and "clinical trials" and "interventions". Manuscripts that met the objective of this study were included for further evaluations. RESULTS: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon ß-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aß) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. CONCLUSION: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aß, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

Exploratory Factor Analysis of SCL90-R Symptoms Relevant to Psychosis.

OBJECTIVE: Inconsistent results have been reported regarding the symptom dimensions relevant to psychosis in symptoms check list revised (SCL90-R), i.e., "psychoticism" and "paranoid ideation". Therefore, some studies have suggested different factor structures for questions of these two dimensions, and proposed two newly defined dimensions of "schizotypal signs" and "schizophrenia nuclear symptoms". We conducted an exploratory factor analysis on the items of these two dimensions in a general population sample in Iran. METHOD: A total of 2158 subjects residing in Southern Tehran (capital of Iran) were interviewed using the psychoticism and paranoid ideation questions in SCL90-R to assess severity of these symptom dimensions. Factor analysis was done through SAS 9.1.3 PROC FACTOR using Promax rotation (power=3) on the matrix of "polychoric correlations among variables" as the input data. RESULTS: Two factors were retained by the proportion criterion. Considering loadings >= 0.5 as minimum criteria for factor loadings, 7 out of 10 questions from psychoticism, and 3 out of 6 questions from paranoid ideation were retained, and others were eliminated. The factor labels proposed by the questionnaire suited the extracted factors and were retained. Internal consistency for each of the dimensions was acceptable (Cronbach's alpha 0.7 and 0.74 for paranoid ideation and psychoticism respectively). Composite scores showed a half-normal distribution for both dimensions which is predictable for instruments that detect psychotic symptoms. CONCLUSION: Results were in contrast with similar studies, and questioned them by suggesting a different factor structure obtained from a statistically large population. The population in a developing nation (Iran) in this study and the socio-cultural differences in developed settings are the potential sources for discrepancies between this analysis and previous reports.