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

Area of Science:

• Neuroscience
• Genetics
• Bioinformatics

Background:

• Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline.
• Alternative splicing events (ASEs) are implicated in age-related diseases, including neurodegenerative disorders.
• Understanding cell-level ASEs in AD brain tissue is crucial for elucidating disease mechanisms.

Purpose of the Study:

• To comprehensively detect and analyze cell-level alternative splicing events in postmortem Alzheimer's disease brain tissue.
• To identify novel splicing and expression alterations specific to different cell types in the AD brain.
• To provide a new strategy for identifying ASEs in neurodegeneration.

Main Methods:

• Utilized bioinformatics pipelines on bulk RNA sequencing data sorted by cell types.
• Analyzed two single-cell RNA sequencing studies from the prefrontal cortex.
• Focused on detecting cell-level ASEs in Alzheimer's disease postmortem brain samples.

Main Results:

• Identified previously overlooked splicing and expression changes in AD patient brains at the cellular level.
• Observed alterations in chaperone transcripts (e.g., CLU, PTGDS, HSP90AA1) in specific cell types like astrocytes, neurons, and microglia.
• Detected changes in novel transcripts and structural alterations in long non-coding RNAs (lncRNAs) such as MEG3 in neurons, associated with the splicing factor DDX5.

Conclusions:

• This study presents a novel strategy for identifying cell-level ASEs in neurodegenerative diseases like AD.
• Revealed cell type-specific splicing alterations in AD, highlighting the importance of cellular context.
• Findings may aid in understanding the link between alternative splicing and neurodegenerative disease outcomes.