Amyloid and aging reshape glial waste management in APP/PS1 mice

Several IgM-reactive structures have recently been proposed as components of glial and meningeal waste-handling pathways in mice: Periodic Acid-Schiff (PAS)-positive polyglucosan granules, extraparenchymal (EP) IgM + granules, and a population of IgM + astrocytes. Here, we analyzed brain specimens to describe how these three structures change with age and amyloid pathology in APPswe/PS1dE9 female mice and C57BL/6 littermate controls at 3, 6, 12, and 22 months of age. PAS granules increased markedly with age and also with amyloid pathology, particularly in hippocampal and piriform cortical regions. In contrast, EP granules were most abundant in young animals and declined progressively with age. IgM + astrocytes increased robustly with aging and were consistently more abundant in APP/PS1 mice than in controls. Triple immunofluorescence revealed that IgM + astrocytes co-express the complement component C3, indicating a complement-engaged reactive phenotype. Collectively, these findings reveal that aging and amyloid pathology influence a neuropathological reconfiguration of multiple elements within the brain’s waste-handling architecture. This remodeling reflects a shift from early-life extraparenchymal structures toward late-life intracellular sequestration and complement-mediated astrocytic responses, highlighting how glial and meningeal pathways respond to chronic proteopathic stress and identifies potential targets to describe waste management in aging and Alzheimer’s disease.