Five miRNAs (miR-5132-5p, miR-764-3p, miR-223-3p, miR-145-5p, and miR-122-5p), ten TFs (Mxi1, Nfatc4, Rxrg, Zfp523, Foxj2, Nk圆-1, Klf4, Klf5, Csrnp1, and Prdm6), and seven target genes (Serpine1, Nedd4l, Pxn, Col1a1, Plec, Trip12, and Tpm1) were chosen as the significant nodes to construct feed-forward loops (FFLs). The miRNA-TF-target gene network was constructed, showing 523 nodes and 7237 edges. DEGs, DEMs, and DETFs were discriminated between rats with 2VO and sham rats in the cortex, as shown by the 13 aberrantly expressed miRNAs, 805 mRNAs, and 63 TFs. The results showed that rats with 2VO had declined cognitive abilities and neuronal loss in the cortex than sham rats. Differentially expressed genes (DEGs), miRNAs (DEMs), and TFs (DETFs) were identified using RNA sequencing, and their interaction networks were constructed using Cytoscape. Therefore, this work investigated the aberrantly expressed miRNAs, TFs, corresponding target genes, and their co-regulatory networks in the cortex of rats with bilateral common carotid artery occlusion (2VO) to uncover the potential mechanism and biomarkers of VaD. microRNAs (miRNAs) and transcription factors (TFs) are considered regulatory factors of genes involved in many diseases. Vascular dementia (VaD) is the second most common form of dementia with uncertain mechanisms and no effective treatments. We believe that further investigation using larger sample sizes will contribute to the accurate classification of subtypes of dementia. Our study demonstrates the potential of blood-based biomarkers for use in dementia-subtype prediction models. Moreover, MCU and CASP3, which are known to be associated with DLB pathogenesis, were identified from our DLB-specific target genes. Network analysis of miRNA target genes revealed important hub genes, SRC and CHD3, associated with the AD pathogenesis. We constructed a final prediction model using 46 miRNAs, which classified dementia patients from an independent validation set into four subtypes of dementia. We used this data to construct dementia subtype prediction models based on penalized regression models with the multiclass classification. We conducted a comprehensive miRNA expression analysis of serum samples from 1348 Japanese dementia patients, composed of four subtypes-Alzheimer’s disease (AD), vascular dementia, dementia with Lewy bodies (DLB), and normal pressure hydrocephalus-and 246 control subjects. Circulating microRNAs (miRNAs) have recently gained attention as easily accessible and non-invasive biomarkers.
There are many subtypes of dementia, and identification of diagnostic biomarkers that are minimally-invasive, low-cost, and efficient is desired. The miRNAs profiles reported in this paper pave the way to translational applications to molecular VaD diagnosis, but they also should allow to further investigate on its molecular bases. Furthermore, the concurrent downregulation of both miR-10b* and miR-130b-3p in VaD showed an AUC of 0.789 (p>0.0001) with 75% of sensitivity and 72% of specificity, while an AUC of 0.789 (p>0.0001) with 92% of sensitivity and 81% of specificity was found for both in AD. ROC curves demonstrated that decreased plasma levels of miR-10b*, miR29a-3p and miR-130b-3p allow to discriminate VaD and AD patients from NCs.
A negative correlation was detected between miR-29a and miR-130b expression and cognitive impairment in VaD and AD, respectively. These miRNAs also were found to be significantly downregulated in a matched cohort of AD patients, but miR-130b-3p levels were lower in AD than in VaD. By exploiting TaqMan Low Density Arrays and single TaqMan assays, miR-10b*, miR29a-3p and miR-130b-3p were discovered and validated as significantly downregulated DE cmiRNAs in VaD patients compared to unaffected controls (NCs). We hypothesized that differentially expressed (DE) cmiRNAs in plasma from VaD patients could be applied to diagnose VaD through liquid biopsies these profiles also could allow to start investigating VaD molecular bases. MiRNAs, which perform critically important biomolecular roles within cell networks, are also found in biological fluids as circulating miRNAs (cmiRNAs). VaD biomolecular bases have been poorly characterized, but vascular-linked factors affecting the CNS and its functions are generally hypothesized to perform a major role, together with cardiovascular and immunological factors. Among dementias, it is second by incidence after Alzheimer's Dementia (AD). Vascular Dementia (VaD) is a pathogenetically heterogeneous neuropsychiatric syndrome, mainly characterized by cognitive impairment.
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