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

Abstract

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.

Long-read RNA-seq demarcatescis- andtrans-directed alternative RNA splicing

“…A remarkable example is the gene UBC, where the linkage direction is almost completely reversed in AD compared to controls. Global alterations in splicing are increasingly appreciated in AD brains 46,[58][59][60][61] , and here we present a unique approach to identify disease-specific regulation with a small cohort size. This notion calls for expanding the current focus of identifying disease-enriched mutations to disease-specific functions of genetic alterations.…”

Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer’s Disease

“…However, recent studies have revealed that changes in gene expression patterns of AD-related genes strongly impact neuronal function and neurodegeneration. In fact, activation and inactivation of transcription (Jiang et al 2013 ; Yang et al 2023 ) and translation factors (Oliveira and Klann 2022 ), expression of non-coding RNA species (Zhou et al 2019 ), alternative splicing (Biamonti et al 2021 ; Farhadieh and Ghaedi 2023 ), and epigenetic mechanisms (Sharma et al 2020 ) may play a role in the pathogenesis of AD (Bagyinszky et al 2020 ).…”