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Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective

Alzheimer’s disease (AD) is a neurodegenerative disease with no effective cure that attacks the brain’s cells resulting in memory loss and changes in behavior and language skills. Alternative splicing is a highly regulated process influenced by specific cell types and has been implicated in age-rela...

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Autores principales: Farhadieh, Mohammad-Erfan, Ghaedi, Kamran
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10548223/
https://www.ncbi.nlm.nih.gov/pubmed/37799732
http://dx.doi.org/10.3389/fnmol.2023.1237874
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author Farhadieh, Mohammad-Erfan
Ghaedi, Kamran
author_facet Farhadieh, Mohammad-Erfan
Ghaedi, Kamran
author_sort Farhadieh, Mohammad-Erfan
collection PubMed
description Alzheimer’s disease (AD) is a neurodegenerative disease with no effective cure that attacks the brain’s cells resulting in memory loss and changes in behavior and language skills. Alternative splicing is a highly regulated process influenced by specific cell types and has been implicated in age-related disorders such as neurodegenerative diseases. A comprehensive detection of alternative splicing events (ASEs) at the cellular level in postmortem brain tissue can provide valuable insights into AD pathology. Here, we provided cell-level ASEs in postmortem brain tissue by employing bioinformatics pipelines on a bulk RNA sequencing study sorted by cell types and two single-cell RNA sequencing studies from the prefrontal cortex. This comprehensive analysis revealed previously overlooked splicing and expression changes in AD patient brains. Among the observed alterations were changed in the splicing and expression of transcripts associated with chaperones, including CLU in astrocytes and excitatory neurons, PTGDS in astrocytes and endothelial cells, and HSP90AA1 in microglia and tauopathy-afflicted neurons, which were associated with differential expression of the splicing factor DDX5. In addition, novel, unknown transcripts were altered, and structural changes were observed in lncRNAs such as MEG3 in neurons. This work provides a novel strategy to identify the notable ASEs at the cell level in neurodegeneration, which revealed cell type-specific splicing changes in AD. This finding may contribute to interpreting associations between splicing and neurodegenerative disease outcomes.
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spelling pubmed-105482232023-10-05 Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective Farhadieh, Mohammad-Erfan Ghaedi, Kamran Front Mol Neurosci Molecular Neuroscience Alzheimer’s disease (AD) is a neurodegenerative disease with no effective cure that attacks the brain’s cells resulting in memory loss and changes in behavior and language skills. Alternative splicing is a highly regulated process influenced by specific cell types and has been implicated in age-related disorders such as neurodegenerative diseases. A comprehensive detection of alternative splicing events (ASEs) at the cellular level in postmortem brain tissue can provide valuable insights into AD pathology. Here, we provided cell-level ASEs in postmortem brain tissue by employing bioinformatics pipelines on a bulk RNA sequencing study sorted by cell types and two single-cell RNA sequencing studies from the prefrontal cortex. This comprehensive analysis revealed previously overlooked splicing and expression changes in AD patient brains. Among the observed alterations were changed in the splicing and expression of transcripts associated with chaperones, including CLU in astrocytes and excitatory neurons, PTGDS in astrocytes and endothelial cells, and HSP90AA1 in microglia and tauopathy-afflicted neurons, which were associated with differential expression of the splicing factor DDX5. In addition, novel, unknown transcripts were altered, and structural changes were observed in lncRNAs such as MEG3 in neurons. This work provides a novel strategy to identify the notable ASEs at the cell level in neurodegeneration, which revealed cell type-specific splicing changes in AD. This finding may contribute to interpreting associations between splicing and neurodegenerative disease outcomes. Frontiers Media S.A. 2023-09-20 /pmc/articles/PMC10548223/ /pubmed/37799732 http://dx.doi.org/10.3389/fnmol.2023.1237874 Text en Copyright © 2023 Farhadieh and Ghaedi. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Molecular Neuroscience
Farhadieh, Mohammad-Erfan
Ghaedi, Kamran
Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective
title Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective
title_full Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective
title_fullStr Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective
title_full_unstemmed Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective
title_short Analyzing alternative splicing in Alzheimer’s disease postmortem brain: a cell-level perspective
title_sort analyzing alternative splicing in alzheimer’s disease postmortem brain: a cell-level perspective
topic Molecular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10548223/
https://www.ncbi.nlm.nih.gov/pubmed/37799732
http://dx.doi.org/10.3389/fnmol.2023.1237874
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