Single-nucleus analysis reveals oxidative stress in Down syndrome basal forebrain neurons at birth.

Introduction: Basal forebrain cholinergic neurons (BFCNs) are integral to learning, attention, and memory, and are prone to degeneration in Down syndrome (DS), Alzheimer's disease, and other neurodegenerative diseases. However, the mechanisms that lead to the degeneration of these neurons are not known.

Methods: Single-nucleus gene expression and ATAC sequencing were performed on postmortem human basal forebrain from unaffected control and DS tissue samples at 0-2 years of age (n=4 each).

Results: Sequencing analysis of postmortem human basal forebrain identifies gene expression differences in DS early in life. Genes encoding proteins associated with energy metabolism pathways, specifically oxidative phosphorylation and glycolysis, and genes encoding antioxidant enzymes are upregulated in DS BFCNs.

Discussion: Multiomic analyses reveal that energy metabolism may be disrupted in DS BFCNs by birth. Increased oxidative phosphorylation and the accumulation of reactive oxygen species byproducts may be early contributors to DS BFCN neurodegeneration.