RNA-Seq analysis of the parietal cortex in Alzheimer's disease reveals alternatively spliced isoforms related to lipid metabolism

2013 ◽  
Vol 536 ◽  
pp. 90-95 ◽  
Author(s):  
James D. Mills ◽  
Thomas Nalpathamkalam ◽  
Heidi I.L. Jacobs ◽  
Caroline Janitz ◽  
Daniele Merico ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Metabolism ◽  
Parietal Cortex ◽  
Rna Seq ◽  
Alternatively Spliced

scholarly journals Proteogenomics Reveals Orthologous Alternatively Spliced Proteoforms in the Same Human and Mouse Brain Regions with Differential Abundance in an Alzheimer’s Disease Mouse Model

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1583
Author(s):  
Esdras Matheus Gomes da Silva ◽  
Letícia Graziela Costa Santos ◽  
Flávia Santiago de Oliveira ◽  
Flávia Cristina de Paula Freitas ◽  
Vinícius da Silva Coutinho Parreira ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Shotgun Proteomics ◽  
Transcript Level ◽  
Brain Regions ◽  
Rna Seq ◽  
Differential Abundance ◽  
Alternatively Spliced ◽  
Ad Mouse Model

Alternative splicing (AS) may increase the number of proteoforms produced by a gene. Alzheimer’s disease (AD) is a neurodegenerative disease with well-characterized AS proteoforms. In this study, we used a proteogenomics strategy to build a customized protein sequence database and identify orthologous AS proteoforms between humans and mice on publicly available shotgun proteomics (MS/MS) data of the corpus callosum (CC) and olfactory bulb (OB). Identical proteotypic peptides of six orthologous AS proteoforms were found in both species: PKM1 (gene PKM/Pkm), STXBP1a (gene STXBP1/Stxbp1), Isoform 3 (gene HNRNPK/Hnrnpk), LCRMP-1 (gene CRMP1/Crmp1), SP3 (gene CADM1/Cadm1), and PKCβII (gene PRKCB/Prkcb). These AS variants were also detected at the transcript level by publicly available RNA-Seq data and experimentally validated by RT-qPCR. Additionally, PKM1 and STXBP1a were detected at higher abundances in a publicly available MS/MS dataset of the AD mouse model APP/PS1 than its wild type. These data corroborate other reports, which suggest that PKM1 and STXBP1a AS proteoforms might play a role in amyloid-like aggregate formation. To the best of our knowledge, this report is the first to describe PKM1 and STXBP1a overexpression in the OB of an AD mouse model. We hope that our strategy may be of use in future human neurodegenerative studies using mouse models.

scholarly journals Role of the lncRNA BACE1-AS in shared disease mechanisms between heart failure and Alzheimer's disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
S Greco ◽  
A Made' ◽  
A.S Tascini ◽  
J Garcia Manteiga ◽  
S Castelvecchio ◽  
...  
Keyword(s):  
Heart Failure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
In Situ Hybridization ◽  
Cell Apoptosis ◽  
Common Disease ◽  
Funding Source ◽  
Mrna Levels ◽  
Rna Seq

Abstract Background BACE1 encodes for β-secretase, the key enzyme involved in β-amyloid (βA) generation, a peptide well known for its involvement in Alzheimer's disease (AD). Of note, heart failure (HF) and AD share several risk factors and effectors. We recently showed that, in the heart of ischemic HF patients, the levels of both BACE1, its antisense RNA BACE1-AS and βA are all increased. BACE1-AS positively regulates the expression of BACE1, triggering βA intracellular accumulation, and its overexpression or βA administration induce cardiovascular-cell apoptosis. Aim To characterize the transcripts of the BACE1 locus and to investigate the molecular mechanisms underpinning BACE1-AS regulation of cell vitality. Methods By PCR and sequencing, we studied in the heart the expression of a variety of antisense BACE1 transcripts predicted by FANTOM CAT Epigenome. We studied BACE1 RNA stability by BrdU pulse chase experiments (BRIC assay). The cellular localization of BACE1-AS RNA was investigated by in situ hybridization assay. BACE1-AS binding RNAs were evaluated by BACE1-AS-MS2-Tag pull-down in AC16 cardiomyocytes followed by RNA-seq. Enriched RNAs were validated by qPCR and analysed by bioinformatics comparison with publicly available gene expression datasets of AD brains. Results We readily detected several antisense BACE1 transcripts expressed in AC16 cardiomyocytes; however, only BACE1-AS RNAs overlapping exon 6 of BACE1 positively regulated BACE1 mRNA levels, acting by increasing its stability. BACE1 silencing reverted cell apoptosis induced by BACE1-AS expression, indicating that BACE1 is a functional target of BACE1-AS. However, in situ hybridization experiments indicated a mainly nuclear localization for BACE1-AS, which displayed a punctuated distribution, compatible with chromatin association and indicative of potential additional targets. To identify other BACE1-AS binding RNAs, a BACE1-AS-MS2-tag pull-down was performed and RNA-seq of the enriched RNAs identified 698 BACE1-AS interacting RNAs in cardiomyocytes. Gene ontology of the BACE1-AS binding RNAs identified categories of relevance for cardiovascular or neurological diseases, such as dopaminergic synapse, glutamatergic synapse, calcium signalling pathway and voltage-gated channel activity. In spite of the differences between brain and heart transcriptomes, BACE1-AS-interacting RNAs identified in cardiomyocytes were significantly enriched in transcripts differentially expressed in AD brains as well as in RNAs expressed by enhancer genomic regions that are significantly hypomethylated in AD brains. Conclusions These data shed a new light on the complexity of BACE1-AS locus and on the existence of RNAs interacting with BACE1-AS with a potential as enhancer-RNAs. Moreover, the dysregulation of the BACE1-AS/BACE1/βA pathway may be a common disease mechanism shared by cardiovascular and neurological degenerative diseases. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Italian Health Ministery_Ricerca Corrente 2020

scholarly journals A new non-aggregative splicing isoform of human Tau is decreased in Alzheimer’s disease

2021 ◽  
Author(s):  
Vega García-Escudero ◽  
Daniel Ruiz-Gabarre ◽  
Ricardo Gargini ◽  
Mar Pérez ◽  
Esther García ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neuroblastoma Cells ◽  
Rna Seq ◽  
Human Neuroblastoma Cells ◽  
Human Neuroblastoma ◽  
Post Translational Modifications ◽  
Protein Levels ◽  
Tau Isoform ◽  
Human Specific

AbstractTauopathies, including Alzheimer’s disease (AD) and frontotemporal lobar degeneration with Tau pathology (FTLD-tau), are a group of neurodegenerative disorders characterized by Tau hyperphosphorylation. Post-translational modifications of Tau such as phosphorylation and truncation have been demonstrated to be an essential step in the molecular pathogenesis of these tauopathies. In this work, we demonstrate the existence of a new, human-specific truncated form of Tau generated by intron 12 retention in human neuroblastoma cells and, to a higher extent, in human RNA brain samples, using qPCR and further confirming the results on a larger database of human RNA-seq samples. Diminished protein levels of this new Tau isoform are found by Westernblotting in Alzheimer’s patients’ brains (Braak I n = 3; Braak II n = 6, Braak III n = 3, Braak IV n = 1, and Braak V n = 10, Braak VI n = 8) with respect to non-demented control subjects (n = 9), suggesting that the lack of this truncated isoform may play an important role in the pathology. This new Tau isoform exhibits similar post-transcriptional modifications by phosphorylation and affinity for microtubule binding, but more interestingly, is less prone to aggregate than other Tau isoforms. Finally, we present evidence suggesting this new Tau isoform could be linked to the inhibition of GSK3β, which would mediate intron 12 retention by modulating the serine/arginine rich splicing factor 2 (SRSF2). Our results show the existence of an important new isoform of Tau and suggest that further research on this less aggregation-prone Tau may help to develop future therapies for Alzheimer’s disease and other tauopathies.

Decreased trkA neurotrophin receptor expression in the parietal cortex of patients with Alzheimer's disease

1998 ◽  
Vol 241 (2-3) ◽  
pp. 151-154 ◽  
Author(s):  
Christoph Hock ◽  
Klaus Heese ◽  
Franz Müller-Spahn ◽  
Christine Hulette ◽  
Carlyn Rosenberg ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Parietal Cortex ◽  
Receptor Expression ◽  
Neurotrophin Receptor

scholarly journals MicroRNA-Seq Data Analysis Pipeline to Identify Blood Biomarkers for Alzheimer's Disease from Public Data

2015 ◽  
Vol 10 ◽  
pp. BMI.S25132 ◽  
Author(s):  
Jun-ichi Satoh ◽  
Yoshihiro Kino ◽  
Shumpei Niida
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Data Analysis ◽  
Small Rna ◽  
Small Rna Sequencing ◽  
Rna Seq ◽  
Analysis Pipeline ◽  
Web Based ◽  
Public Data ◽  
Data Analysis Pipeline

Background Alzheimer's disease (AD) is the most common cause of dementia with no curative therapy currently available. Establishment of sensitive and non-invasive biomarkers that promote an early diagnosis of AD is crucial for the effective administration of disease-modifying drugs. MicroRNAs (miRNAs) mediate posttranscriptional repression of numerous target genes. Aberrant regulation of miRNA expression is implicated in AD pathogenesis, and circulating miRNAs serve as potential biomarkers for AD. However, data analysis of numerous AD-specific miRNAs derived from small RNA-sequencing (RNA-Seq) is most often laborious. Methods To identify circulating miRNA biomarkers for AD, we reanalyzed a publicly available small RNA-Seq dataset, composed of blood samples derived from 48 AD patients and 22 normal control (NC) subjects, by a simple web-based miRNA data analysis pipeline that combines omiRas and DIANA miRPath. Results By using omiRas, we identified 27 miRNAs expressed differentially between both groups, including upregulation in AD of miR-26b-3p, miR-28–3p, miR-30c-5p, miR-30d-5p, miR-148b-5p, miR-151a-3p, miR-186–5p, miR-425–5p, miR-550a-5p, miR-1468, miR-4781–3p, miR-5001–3p, and miR-6513–3p and downregulation in AD of let-7a-5p, let-7e-5p, let-7f-5p, let-7g-5p, miR-15a-5p, miR-17–3p, miR-29b-3p, miR-98–5p, miR-144–5p, miR-148a-3p, miR-502–3p, miR-660–5p, miR-1294, and miR-3200–3p. DIANA miRPath indicated that miRNA-regulated pathways potentially down– regulated in AD are linked with neuronal synaptic functions, while those upregulated in AD are implicated in cell survival and cellular communication. Conclusions The simple web-based miRNA data analysis pipeline helps us to effortlessly identify candidates for miRNA biomarkers and pathways of AD from the complex small RNA–Seq data.

scholarly journals scREAD: A Single-Cell RNA-Seq Database for Alzheimer's Disease

iScience ◽  
2020 ◽  
Vol 23 (11) ◽  
pp. 101769
Author(s):  
Jing Jiang ◽  
Cankun Wang ◽  
Ren Qi ◽  
Hongjun Fu ◽  
Qin Ma
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Cell ◽  
Rna Seq

scholarly journals Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU

2020 ◽  
Vol 21 (19) ◽  
pp. 7079
Author(s):  
Seonggyun Han ◽  
Kwangsik Nho ◽  
Younghee Lee
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Alternative Splicing ◽  
Genetic Variants ◽  
Temporal Cortex ◽  
Integrative Approach ◽  
Splicing Regulation ◽  
Rna Seq ◽  
Risk Variant

Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of CLU on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership—Alzheimer’s Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain—the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of CLU; as the number of alternative alleles (G) increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation.

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