iPSC-derived cortical neurons to study sporadic Alzheimer disease: A transcriptome comparison with post-mortem brain...

Area of Science:

• Neuroscience
• Stem Cell Biology
• Genetics

Background:

• Alzheimer's disease (AD) is the leading cause of dementia, with sporadic AD (sAD) accounting for 95% of cases.
• sAD arises from complex genetic and environmental interactions, involving factors termed "Alzheimerogens" like heavy metals and pesticides.
• Neuroinflammation is a key factor in AD pathogenesis, and in vitro models are needed to study Alzheimerogen effects.

Purpose of the Study:

• To evaluate induced pluripotent stem cell (iPSC)-derived cortical neurons as an in vitro model for studying Alzheimer's disease (AD).
• To compare transcriptomic changes in sAD iPSC-derived neurons with differentially expressed genes (DEGs) from post-mortem AD brain tissue.
• To investigate the effects of specific Alzheimerogens (copper, fipronil, and inflammatory cytokines) on these iPSC-derived neurons.

Main Methods:

• Generated and characterized iPSC-derived cortical neurons from sAD patients.
• Performed transcriptomic analysis (RNA sequencing) on sAD iPSC-derived neurons.
• Exposed iPSC-derived neurons to copper(II)chloride, fipronil sulfone, and an inflammatory cytokine cocktail.

Main Results:

• sAD iPSC-derived neurons exhibited transcriptomic changes mirroring AD-related processes, identifying more DEGs than post-mortem brain tissue.
• Cytokine exposure upregulated immune-related genes.
• Copper exposure altered genes involved in lipid and cholesterol metabolism, known AD-related pathways.
• Fipronil exposure did not yield significant transcriptomic changes, suggesting potential need for altered experimental conditions.

Conclusions:

• iPSC-derived cortical neurons serve as a valuable in vitro model for AD research.
• This model aids in identifying novel Alzheimerogens and elucidating AD-related molecular mechanisms.
• The findings support the utility of iPSC-derived neurons for investigating sporadic AD pathogenesis.