Spatiotemporal characterization of glial cell activation in an Alzheimer's disease model by spatially resolved transcriptomics.

The molecular changes that occur with the progression of Alzheimer's disease (AD) are well known, but an understanding of the spatiotemporal heterogeneity of changes in the brain is lacking. Here, we investigated the spatially resolved transcriptome in a 5XFAD AD model at different ages to understand regional changes at the molecular level. Spatially resolved transcriptomic data were obtained from 5XFAD AD models and age-matched control mice. Differentially expressed genes were identified using spots clustered by anatomical structures. Gene signatures of activation of microglia and astrocytes were calculated and mapped on the spatially resolved transcriptomic data. We identified early alterations in the white matter (WM) of the AD model before the definite accumulation of amyloid plaques in the gray matter (GM). Changes in the early stage of the disease involved primarily glial cell activation in the WM, whereas the changes in the later stage of pathology were prominent in the GM. We confirmed that disease-associated microglia (DAM) and astrocyte (DAA) signatures also showed initial changes in WM and that activation spreads to GM. Trajectory inference using microglial gene sets revealed the subdivision of DAMs with different spatial patterns. Taken together, these results help to understand the spatiotemporal changes associated with reactive glial cells as a major pathophysiological characteristic of AD. The heterogeneous spatial molecular changes apply to identifying diagnostic and therapeutic targets caused by amyloid accumulation in AD.