The terminal zone of axonal projections from the layer II MEC neurons with the granular layer (gl) and the middle- molecular layers (mml) which express the human tau transgene developed early accumulation of misfolded tau (Alz50 staining, A) which intensified up to 12 months of age. At 18 months, the terminal staining with Alz50 became fainter with DG neurons in the granular cell layer becoming more prominently stained. At 21 and 24 months, Alz50 staining in the terminal zone was patchy indicating degeneration of Alz50 containing axons (Scale bar 100 μm, A). Concomitant with this axonal degeneration, we observe increased microglial activation (Iba1 staining) at 24 months of age in rTgTauEC mice in the molecular layer of the dentate gyrus (B) Double Immunohistolabeling with Alz50 and Iba1 shows that the patches of Alz50 staining of the axon terminals in the middle molecular layer of dentate gyrus are surrounded by activated microglia (C, shown in higher magnification in the inset. Scale bars, 50 μm left panel), and 20 μm right panel). GFAP labeled astrocytes are more prevalent in rTgTauEC brain than controls (D, Scale bar, 50 μm). Co-localization of GFAP and PHF1-positive aggregates indicate uptake of tau by astrocytes (E, Scale bar, 20 μm).