Accumulation of Vesicle-Associated Human Tau in Distal Dendrites Drives Degeneration and Tau Secretion in an In Situ Cellular Tauopathy Model
Evidence for the transport and distribution of hyperphosphorylated tau with low MT binding affinity into distal dendrites. (a) Examples of somatodendritic profiles from ABCs expressing high tau levels immunolabeled with phosphospecific Abs to epitopes on human tau (described in Figure 7) that identify low, medium, and high degrees of tau association with MTs. The green channel shows immunolabel Abs identifying tau with low (9G3, 12E8), medium (AT180, PHF1), and high (Tau1, Tau5, Tau12) MT affinity showing characteristically different distributions relative to the POD and to “total” tau distribution as shown by anti-GFP tag immunolabel (red channel of all images). Markers of non-MT-associated tau (9G3 and 12E8, right panels) are the most concentrated at the POD (line) and the least associated with MT-rich proximal dendrites (asterisks). By contrast, markers of dephosphorylated tau (e.g., Tau1—bottom left panel) are less concentrated at the POD and are largely codistributed with tubulin (top left), AT180 and PHF1, which mark intermediate states of MT affinity and show an intermediate distribution pattern. (b) Quantitation of the relationships illustrated by the sections shown in (a). Tau immunolabel intensity was normalized to the level seen at the POD for each antibody in each section examined and the relative intensity of immunolabel shown. Differences in distribution between proximal dendrites the POD and degenerating dendrites distal to the POD were highly significant for each antibody examined (all values <0.005, Student’s -test). Markers of low-affinity tau (green) were significantly lower than medium-(blue) and high- (tan) MT-affinity markers in proximal dendrites ( and 0.001, resp.), whereas all tau markers declined to a level significantly below that of the POD in degenerating distal dendrites (all values <0.001). Bars show standard error. (c) A schematic diagram summarizing the relationship between the distribution of tau with low (9G3, 12E8), medium (AT180, PHF1), and high (Tau1, Tau5, Tau12) MT affinity illustrated in (a) and analyzed in (b). Scale bars: (a) 100 μm.
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