scholarly journals Systematic Identification of circRNAs in Alzheimer’s Disease

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1258
Author(s):  
Kyle R. Cochran ◽  
Kirtana Veeraraghavan ◽  
Gautam Kundu ◽  
Krystyna Mazan-Mamczarz ◽  
Christopher Coletta ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Temporal Cortex ◽  
Circular Rnas ◽  
Sequencing Data ◽  
Cognitively Normal ◽  
Vesicular Traffic ◽  
Wide Range ◽  
Systematic Identification ◽  
Influence Gene Expression

Mammalian circRNAs are covalently closed circular RNAs often generated through backsplicing of precursor linear RNAs. Although their functions are largely unknown, they have been found to influence gene expression at different levels and in a wide range of biological processes. Here, we investigated if some circRNAs may be differentially abundant in Alzheimer’s Disease (AD). We identified and analyzed publicly available RNA-sequencing data from the frontal lobe, temporal cortex, hippocampus, and plasma samples reported from persons with AD and persons who were cognitively normal, focusing on circRNAs shared across these datasets. We identified an overlap of significantly changed circRNAs among AD individuals in the various brain datasets, including circRNAs originating from genes strongly linked to AD pathology such as DOCK1, NTRK2, APC (implicated in synaptic plasticity and neuronal survival) and DGL1/SAP97, TRAPPC9, and KIF1B (implicated in vesicular traffic). We further predicted the presence of circRNA isoforms in AD using specialized statistical analysis packages to create approximations of entire circRNAs. We propose that the catalog of differentially abundant circRNAs can guide future investigation on the expression and splicing of the host transcripts, as well as the possible roles of these circRNAs in AD pathogenesis.

scholarly journals Multi-tissue neocortical transcriptome-wide association study implicates 8 genes across 6 genomic loci in Alzheimer’s disease

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Jake Gockley ◽  
Kelsey S. Montgomery ◽  
William L. Poehlman ◽  
Jesse C. Wiley ◽  
Yue Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Prefrontal Cortex ◽  
Association Study ◽  
Inferior Frontal Gyrus ◽  
Temporal Cortex ◽  
European Ancestry ◽  
Common Genetic Variants ◽  
Wide Range

Abstract Background Alzheimer’s disease (AD) is an incurable neurodegenerative disease currently affecting 1.75% of the US population, with projected growth to 3.46% by 2050. Identifying common genetic variants driving differences in transcript expression that confer AD risk is necessary to elucidate AD mechanism and develop therapeutic interventions. We modify the FUSION transcriptome-wide association study (TWAS) pipeline to ingest gene expression values from multiple neocortical regions. Methods A combined dataset of 2003 genotypes clustered to 1000 Genomes individuals from Utah with Northern and Western European ancestry (CEU) was used to construct a training set of 790 genotypes paired to 888 RNASeq profiles from temporal cortex (TCX = 248), prefrontal cortex (FP = 50), inferior frontal gyrus (IFG = 41), superior temporal gyrus (STG = 34), parahippocampal cortex (PHG = 34), and dorsolateral prefrontal cortex (DLPFC = 461). Following within-tissue normalization and covariate adjustment, predictive weights to impute expression components based on a gene’s surrounding cis-variants were trained. The FUSION pipeline was modified to support input of pre-scaled expression values and support cross validation with a repeated measure design arising from the presence of multiple transcriptome samples from the same individual across different tissues. Results Cis-variant architecture alone was informative to train weights and impute expression for 6780 (49.67%) autosomal genes, the majority of which significantly correlated with gene expression; FDR < 5%: N = 6775 (99.92%), Bonferroni: N = 6716 (99.06%). Validation of weights in 515 matched genotype to RNASeq profiles from the CommonMind Consortium (CMC) was (72.14%) in DLPFC profiles. Association of imputed expression components from all 2003 genotype profiles yielded 8 genes significantly associated with AD (FDR < 0.05): APOC1, EED, CD2AP, CEACAM19, CLPTM1, MTCH2, TREM2, and KNOP1. Conclusions We provide evidence of cis-genetic variation conferring AD risk through 8 genes across six distinct genomic loci. Moreover, we provide expression weights for 6780 genes as a valuable resource to the community, which can be abstracted across the neocortex and a wide range of neuronal phenotypes.

scholarly journals Differentiating Between Healthy Control Participants and Those with Mild Cognitive Impairment Using Volumetric MRI Data

2019 ◽  
Vol 25 (08) ◽  
pp. 800-810 ◽  
Author(s):  
Renée DeVivo ◽  
Lauren Zajac ◽  
Asim Mian ◽  
Anna Cervantes-Arslanian ◽  
Eric Steinberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Frontal Cortex ◽  
Temporal Lobe ◽  
Medial Temporal Lobe ◽  
Temporal Cortex ◽  
Anterior Cingulate ◽  
Cognitively Normal

AbstractObjective:To determine whether volumetric measures of the hippocampus, entorhinal cortex, and other cortical measures can differentiate between cognitively normal individuals and subjects with mild cognitive impairment (MCI).Method:Magnetic resonance imaging (MRI) data from 46 cognitively normal subjects and 50 subjects with MCI as part of the Boston University Alzheimer’s Disease Center research registry and the Alzheimer’s Disease Neuroimaging Initiative were used in this cross-sectional study. Cortical, subcortical, and hippocampal subfield volumes were generated from each subject’s MRI data using FreeSurfer v6.0. Nominal logistic regression models containing these variables were used to identify subjects as control or MCI.Results:A model containing regions of interest (superior temporal cortex, caudal anterior cingulate, pars opercularis, subiculum, precentral cortex, caudal middle frontal cortex, rostral middle frontal cortex, pars orbitalis, middle temporal cortex, insula, banks of the superior temporal sulcus, parasubiculum, paracentral lobule) fit the data best (R2= .7310, whole model test chi-square = 97.16,p&lt; .0001).Conclusions:MRI data correctly classified most subjects using measures of selected medial temporal lobe structures in combination with those from other cortical areas, yielding an overall classification accuracy of 93.75%. These findings support the notion that, while volumes of medial temporal lobe regions differ between cognitively normal and MCI subjects, differences that can be used to distinguish between these two populations are present elsewhere in the brain.

Therapeutic Properties of Several Chemical Compounds from Salvia officinalis L. in Alzheimer’s Disease

2020 ◽  
Vol 21 ◽  
Author(s):  
Georgiana Uță ◽  
Denisa Ștefania Manolescu ◽  
Speranța Avram
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Side Effects ◽  
Chemical Compounds ◽  
Natural Compounds ◽  
Salvia Officinalis ◽  
Chemical Structures ◽  
In Silico Studies ◽  
Wide Range ◽  
Salvia Officinalis L

Background.: Currently, the pharmacological management in Alzheimer's disease is based on several chemical structures, represented by acetylcholinesterase and N-methyl-D-aspartate (NMDA) receptor ligands, with still unclear molecular mechanisms, but severe side effects. For this reason, a challenge for Alzheimer's disease treatment remains to identify new drugs with reduced side effects. Recently, the natural compounds, in particular certain chemical compounds identified in the essential oil of peppermint, sage, grapes, sea buckthorn, have increased interest as possible therapeutics. Objectives.: In this paper, we have summarized data from the recent literature, on several chemical compounds extracted from Salvia officinalis L., with therapeutic potential in Alzheimer's disease. Methods.: In addition to the wide range of experimental methods performed in vivo and in vitro, also we presented some in silico studies of medicinal compounds. Results. Through this mini-review, we present the latest information regarding the therapeutic characteristics of natural compounds isolated from Salvia officinalis L. in Alzheimer's disease. Conclusion.: Thus, based on the information presented, we can say that phytotherapy is a reliable therapeutic method in a neurodegenerative disease.

scholarly journals NLRP3 Inflammasome: A Starring Role in Amyloid-β- and Tau-Driven Pathological Events in Alzheimer’s Disease

2021 ◽  
pp. 1-22
Author(s):  
Mariana Van Zeller ◽  
Diogo M. Dias ◽  
Ana M. Sebastião ◽  
Cláudia A. Valente
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Nlrp3 Inflammasome ◽  
Neuronal Death ◽  
Inflammatory Responses ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Wide Range

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease commonly diagnosed among the elderly population. AD is characterized by the loss of synaptic connections, neuronal death, and progressive cognitive impairment, attributed to the extracellular accumulation of senile plaques, composed by insoluble aggregates of amyloid-β (Aβ) peptides, and to the intraneuronal formation of neurofibrillary tangles shaped by hyperphosphorylated filaments of the microtubule-associated protein tau. However, evidence showed that chronic inflammatory responses, with long-lasting exacerbated release of proinflammatory cytokines by reactive glial cells, contribute to the pathophysiology of the disease. NLRP3 inflammasome (NLRP3), a cytosolic multiprotein complex sensor of a wide range of stimuli, was implicated in multiple neurological diseases, including AD. Herein, we review the most recent findings regarding the involvement of NLRP3 in the pathogenesis of AD. We address the mechanisms of NLRP3 priming and activation in glial cells by Aβ species and the potential role of neurofibrillary tangles and extracellular vesicles in disease progression. Neuronal death by NLRP3-mediated pyroptosis, driven by the interneuronal tau propagation, is also discussed. We present considerable evidence to claim that NLRP3 inhibition, is undoubtfully a potential therapeutic strategy for AD.

Impacts of Iron Metabolism Dysregulation on Alzheimer’s Disease

2021 ◽  
Vol 80 (4) ◽  
pp. 1439-1450
Author(s):  
Najla Jouini ◽  
Zakaria Saied ◽  
Samia Ben Sassi ◽  
Fatma Nebli ◽  
Taieb Messaoud ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Antioxidant System ◽  
Plasma Concentrations ◽  
Normal Brain ◽  
Cognitively Normal ◽  
Iron Trafficking ◽  
Major Species ◽  
Normal Brain Function ◽  
Calcium Magnesium

Background: Iron plays an important role in maintaining cell survival, with normal iron trafficking known to be regulated by the ceruloplasmin-transferrin (Cp-Tf) antioxidant system. Disruption to this system is thought to be detrimental to normal brain function. Objective: To determine whether an imbalance of iron and the proteins involved in its metabolism (ceruloplasmin and transferrin) are linked to Alzheimer’s disease (AD) and to the expression of amyloid-beta (Aβ) peptide 1–42 (Aβ1–42), which is a major species of Aβ, and the most toxic. Methods: We evaluated the concentrations of iron, calcium, magnesium, and Aβ1–42 in the cerebrospinal fluid (CSF) of patients with AD and cognitively normal controls. Correlations between the components of the Cp-Tf antioxidant system in plasma were studied to determine the role of peripheral blood in the onset and/or development of AD. We used commercial ELISA immunoassays to measure Aβ1–42, immunoturbidimetry to quantify ceruloplasmin and transferrin, and colorimetry to quantify iron, calcium, and magnesium. Results: We found that the AD group had lower CSF concentrations of Aβ1–42 (p < 0.001) and calcium (p < 0.001), but a higher CSF concentration of iron (p < 0.001). Significantly lower plasma concentrations of ceruloplasmin (p = 0.003), transferrin (mean, p < 0.001), and iron (p < 0.001) were observed in the AD group than in cognitively normal adults. Moreover, we found a strong interdependence between most of these components. Conclusion: Iron dyshomeostasis has a crucial role in the onset of AD and/or its development. Correcting metal misdistribution is an appealing therapeutic strategy for AD.

scholarly journals Financial Capacity and Regional Cerebral Tau in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer’s Disease Dementia

2020 ◽  
pp. 1-10
Author(s):  
Christopher Gonzalez ◽  
Nicole S. Tommasi ◽  
Danielle Briggs ◽  
Michael J. Properzi ◽  
Rebecca E. Amariglio ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Older Adults ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Early Stage ◽  
Cognitively Normal ◽  
Financial Capacity ◽  
Posterior Cingulate ◽  
Dorsolateral Prefrontal

Background: Financial capacity is often one of the first instrumental activities of daily living to be affected in cognitively normal (CN) older adults who later progress to amnestic mild cognitive impairment (MCI) and Alzheimer’s disease (AD) dementia. Objective: The objective of this study was to investigate the association between financial capacity and regional cerebral tau. Methods: Cross-sectional financial capacity was assessed using the Financial Capacity Instrument –Short Form (FCI-SF) in 410 CN, 199 MCI, and 61 AD dementia participants who underwent flortaucipir tau positron emission tomography from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Linear regression models with backward elimination were used with FCI-SF total score as the dependent variable and regional tau and tau-amyloid interaction as predictors of interest in separate analyses. Education, age sex, Rey Auditory Verbal Learning Test Total Learning, and Trail Making Test B were used as covariates. Results: Significant associations were found between FCI-SF and tau regions (entorhinal: p <  0.001; inferior temporal: p <  0.001; dorsolateral prefrontal: p = 0.01; posterior cingulate: p = 0.03; precuneus: p <  0.001; and supramarginal gyrus: p = 0.005) across all participants. For the tau-amyloid interaction, significant associations were found in four regions (amyloid and dorsolateral prefrontal tau interaction: p = 0.005; amyloid and posterior cingulate tau interaction: p = 0.005; amyloid and precuneus tau interaction: p <  0.001; and amyloid and supramarginal tau interaction: p = 0.002). Conclusion: Greater regional tau burden was modestly associated with financial capacity impairment in early-stage AD. Extending this work with longitudinal analyses will further illustrate the utility of such assessments in detecting clinically meaningful decline, which may aid clinical trials of early-stage AD.

scholarly journals Peripheral Markers of Vascular Endothelial Dysfunction Show Independent but Additive Relationships with Brain-Based Biomarkers in Association with Functional Impairment in Alzheimer’s Disease

2021 ◽  
pp. 1-13
Author(s):  
Jonathan D. Drake ◽  
Alison B. Chambers ◽  
Brian R. Ott ◽  
Lori A. Daiello ◽  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Adhesion ◽  
Adhesion Molecule ◽  
Functional Impairment ◽  
Amyloid Β ◽  
Intercellular Adhesion Molecule ◽  
Csf Biomarkers ◽  
Linear Regression Models ◽  
Cognitively Normal

Background: Cerebrovascular dysfunction confers risk for functional decline in Alzheimer’s disease (AD), yet the clinical interplay of these two pathogenic processes is not well understood. Objective: We utilized Alzheimer’s Disease Neuroimaging Initiative (ADNI) data to examine associations between peripherally derived soluble cell adhesion molecules (CAMs) and clinical diagnostic indicators of AD. Methods: Using generalized linear regression models, we examined cross-sectional relationships of soluble plasma vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-Selectin to baseline diagnosis and functional impairment (clinical dementia rating sum-of-boxes, CDR-SB) in the ADNI cohort (n = 112 AD, n = 396 mild cognitive impairment (MCI), n = 58 cognitively normal). We further analyzed associations of these biomarkers with brain-based AD biomarkers in a subset with available cerebrospinal fluid (CSF) data (n = 351). p-values derived from main effects and interaction terms from the linear regressions were used to assess the relationship between independent and dependent variables for significance (significance level was set at 0.05 a priori for all analysis). Results: Higher mean VCAM-1 (p = 0.0026) and ICAM-1 (p = 0.0189) levels were found in AD versus MCI groups; however, not in MCI versus cognitively normal groups. Only VCAM-1 was linked with CDR-SB scores (p = 0.0157), and APOE ɛ4 genotype modified this effect. We observed independent, additive associations when VCAM-1 and CSF amyloid-β (Aβ 42), total tau, phosphorylated tau (P-tau), or P-tau/Aβ 42 (all <  p = 0.01) were combined in a CDR-SB model; ICAM-1 showed a similar pattern, but to a lesser extent. Conclusion: Our findings indicate independent associations of plasma-based vascular biomarkers and CSF biomarkers with AD-related clinical impairment.

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