Spatiotemporal characterization of glial cell activation in an Alzheimer’s disease model by spatially resolved transcriptome

ABSTRACT The pathophysiological changes that occur with the progression of Alzheimer’s disease (AD) are well known, but understanding the spatiotemporal heterogeneity of the brain is needed. Here, we investigated the spatially resolved transcriptome in a 5XFAD AD model of different ages to understand regional changes at the molecular level. 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 were involved primarily in glial cell activation in WM, whereas the changes were prominent in the later stage of pathology in 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 pathophysiology of AD and provide information for diagnosis and prognosis based on spatiotemporal changes caused by amyloid accumulation in AD.