Isotope Encoded Spatial Biology Identifies Amyloid Plaque-Age-Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity.

Understanding how amyloid beta (Aβ) plaques form and progress to neurotoxicity in Alzheimer's disease remains a significant challenge. This study aims to elucidate the processes involved in Aβ plaque formation and maturation using a knock-in Aβ mouse model (App NL-F/NL-F ). By employing mass spectrometry imaging and stable isotope labeling, we timestamped Aβ plaques from their initial deposition, enabling the spatial tracking of plaque aging. Correlating single-plaque spatial transcriptomics with time since seeding, allowed us to track gene-expression changes specifically associated with plaque age, independent of chronological age of the mouse or disease severity. We found that plaque age, within sections from individual mice aged from 10 to 18 months, negatively correlates with synaptic gene expression. Further, correlation with hyperspectral confocal microscopy using structure-specific dyes revealed a positive link between plaque age and structural maturity, with older plaques identified as more compact and associated with significantly greater synapse loss and toxicity.