Fig. 1.

A new model of the spread of tau pathology in the MTL according to current theory. Stage 1: The first seeds of tau pathology develop in NSCs in the SGZ niche of the DG. Then, they spread from the DG to the EC by retrograde transmission along the connections of the perforant pathway. Stage 2: Seeds of tau pathology spread from the EC to the TEC by both anterograde and retrograde transmission along the multiple connections between the two regions. Because of the massive load of tau pathology accumulated in the TEC, tangles develop here first. At the same time, tangle formation is suppressed (or delayed) in the DG because of the strong clearance activity that usually occurs in the neurogenesis niches. As a result, the transmission of tau pathology from the DG to CA3 is nullified (red cross). Stage 3: Seeds of tau pathology spread from the EC to the CA1 and subiculum along the EC-CA1 and EC-subiculum projections, respectively. In contrast, the seeds of tau pathology would not spread anterogradely to the DG (red cross), because the neuronal connections between the EC and DG are already deteriorated at this stage due to the transmission of tau pathology in the reverse (retrograde) direction in the previous stage (Stage 1). Stage 4. When tau tangles emerge in the CA1 and subiculum (starting from Braak stage II), the DG and CA3 are not yet affected. Figure 1 was produced by Antonio Garcia, scientific illustrator from Bio-Graphics.