Basic Science and Pathogenesis.

Area of Science:

• Neuroscience
• Genetics
• Stem Cell Biology

Background:

• The Presenilin-1 (PSEN1) G206A mutation, prevalent in Puerto Ricans, is linked to Alzheimer disease (AD) with significant age-of-onset (AOO) variability.
• The underlying mechanisms driving this AOO variability in PSEN1 G206A carriers remain unclear.

Purpose of the Study:

• To investigate cell type-specific transcriptomic differences associated with AOO variability in PSEN1 G206A mutation carriers.
• To utilize induced pluripotent stem cells (iPSCs) to model AD pathogenesis and explore molecular underpinnings of disease heterogeneity.

Main Methods:

• Generated spheroid 3D cultures from iPSCs of six PSEN1 G206A carriers (three early AOO, three late AOO).
• Performed single nucleus RNA sequencing (snRNA-seq) on 38,577 nuclei at day 75 of differentiation.
• Analyzed transcriptomic data using Seurat to identify differential gene expression between early and late AOO groups.

Main Results:

• Identified eight cell type clusters, with oligodendrocytes showing the highest PSEN1 expression.
• No significant differences in PSEN1 or substrate expression were found between early and late AOO groups.
• Found decreased expression of genes in presynaptic differentiation, ER stress, neuroinflammation, and lipid metabolism in early vs. late AOO.
• Observed increased expression of vascular, neurodevelopment, and lipid metabolism genes in early vs. late AOO carriers.

Conclusions:

• Transcriptomic alterations in 3D cultures correlate with AOO variability in PSEN1 G206A carriers.
• Pathways including vascular morphogenesis, lipid processing, protein aggregation, and neuronal regulation are implicated in AD AOO variability.
• These findings provide insights into the molecular basis of AD heterogeneity in specific populations.