Cannabinerol Restores mRNA Splicing Defects Induced by β-Amyloid in an In Vitro Model of Alzheimer's Disease: A...

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alzheimer's disease (AD) is linked to amyloid plaques and neurofibrillary tangles, causing cognitive decline.
• RNA splicing dysregulation is increasingly recognized as a factor in AD pathogenesis.
• Previous work showed cannabinerol (CBNR) protects against amyloid-beta-induced cell death and affects splicing gene expression.

Purpose of the Study:

• To investigate if CBNR can reverse RNA splicing defects induced by amyloid-beta (Aβ) in an in vitro Alzheimer's disease model.
• To identify specific splicing events and pathways affected by Aβ and modulated by CBNR.
• To explore potential mechanisms of CBNR's neuroprotective effects related to RNA processing.

Main Methods:

• Utilized RNA-sequencing (RNA-Seq) data from differentiated SH-SY5Y cells exposed to Aβ and/or CBNR.
• Employed the rMATS computational tool to detect differential alternative splicing events (DASEs).
• Performed pathway analysis and investigated retained introns (RIs) and miRNA interactions within DASE regions.

Main Results:

• Identified 96 DASEs regulated by Aβ, all of which were restored by CBNR pre-treatment.
• Pathway analysis revealed enrichment in the "Alzheimer's disease-amyloid secretase pathway".
• Observed increased retained introns with premature stop codons upon Aβ exposure, normalized by CBNR; identified 33 potential DASE/miRNA interactions relevant to AD.

Conclusions:

• CBNR demonstrates a novel ability to restore Aβ-induced splicing defects in an AD model.
• CBNR's neuroprotective effects may be partly mediated by its regulation of mRNA splicing and trans-gene regulation.
• This study is the first to show a cannabinoid's role in regulating mRNA splicing within an Alzheimer's disease context.