Accumulation of Vesicle-Associated Human Tau in Distal Dendrites Drives Degeneration and Tau Secretion in an In Situ Cellular Tauopathy Model
Low-versus high- MT-affinity tau species in ABC dendrites. (a) Schematic of the longest tau isoform showing tau phosphorylation sites. Phosphorylation of proline-directed sites flanking the MTBR (AT180, AT8, PHF1) produces a stoichiometrically graded reduction in MT affinity, whereas phosphorylation of KXGS sequences (S262, S356) within the MTBR region cause pronounced loss of MT binding affinity (12E8, green arrows). Phosphorylation of Y18 identifies fyn-mediated phosphorylation tau (9G3, shaded asterisk). Tau recognized selectively by mAbs specific to nonphosphorylated (Tau12, Tau5) and dephosphorylated (Tau1) sites is largely bound to MTs. (b) Illustration of the different spatial relationship between “low affinity” (9G3+ tau, left) and “high affinity” (Tau5+ tau, center). Tau is red channel, tubulin is green channel, and colocalized label (ImageJ colocalization highlighter threshold 50/50) is blue channel. Note that the central bundle of MTs in the left-hand image is relatively free of 9G3+ tau, whereas tubulin and Tau5 labels are extensively colocalized (center image—no red label is visible). Right image: Section is labeled for low-affinity (9G3, red channel) and high-affinity (Tau 1, green channel) tau. Note that there is considerable colocalization near the central MT bundle (blue channel), which is consistent with the dynamic nature of dendritic MTs. Scale bar: 10 μm.
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