PubMed: 27373205

Pseudophosphorylation of tau at S422 enhances SDS-stable dimer formation and impairs both anterograde and retrograde fast axonal transport.
Experimental neurology
Tiernan CT | Brady ST | Combs B | Counts SE | Cox K | Kanaan NM | Morfini G

Evidence 84b59db24e

The amount of total tau captured with pS422 (detected with the pan-tau antibody, Tau5) was significantly higher in AD compared to control (Fig. 7E; t10 = 6.07, p = 0.0001). The level of pS422 tau that also contained PAD exposed tau (i.e., TNT1 reactive) was significantly higher in AD compared to control (Fig. 7F; t10 = 2.31, p = 0.0435). Similarly, the level of pS422 tau that also contained an oligomeric conformation (i.e., TOC1 reactive) was significantly higher in AD compared to control (Fig. 7G; t10 = 1.51, p = 0.0029).

Evidence 74251db8bb

Compared to monomers, aggregation significantly increased PAD exposure for both hT40 and S422E samples (Fig. 3B; F(1,12) = 685.8, p b 0.0001), as indicated by increased TNT1 reactivity. Aggregation also significantly increased oligomer formation (TOC1 reactivity) compared to monomers in both hT40 and S422E samples (Fig. 3C; F(1,12) = 109.3, p b 0.0001).

Evidence f00f14db7d

In contrast, aggregation of either hT40 or S422E significantly increased the amount of SDS-stable dimers at 180 kDa (Fig. 4C; F(1,12) = 110.0; p b 0.0001), as compared to the levels of these species in the respective monomer samples. Furthermore, S422E aggregation significantly increased the amount of SDS-stable dimers compared to hT40 aggregation (p = 0.03).

Evidence 86a62494fa

As previously reported, perfusion of hT40 monomer had no effect on the rate of anterograde FAT in the squid axoplasm (Fig. 5A), whereas perfusion of hT40 aggregates significantly inhibited anterograde FAT as compared to hT40 monomer (Fig. 5B; Fig. 6A; p = 0.003) (LaPointe et al., 2009b). Neither hT40 monomers nor hT40 aggregates altered the rate of retrograde FAT (Fig. 5A, B; Fig. 6B).

Evidence db8270c505

However, the rate of polymerization (kapparent) did not differ between hT40 tau and S422E tau. At 360 min, a similar intensity of light scattering was observed for hT40 (122.5 ± 1.2) and S422E tau (134.5±1.7) indicating that the extent of aggregate formation was comparable between these two proteins. ThS fluorescence, measured at 360min, alsowas comparable between hT40 aggregates (946.4 ± 73.8) and S422E aggregates (927.9 ± 63.7).

Evidence 43204bf76d

For both tau constructs, there were significantly more oligomer-type aggregates than short or long filaments formed, but no significant difference between the numbers of short or long filament (Fig. 2E; F(2,12) = 86.64, p b 0.0001). S422E did not differ significantly from hT40 in the number of oligomers, short filaments, or long filaments formed (F(1,12) = 0.05, p = 0.83).

Evidence c2edb210b4

In contrast to hT40 monomer, perfusion of S422E monomer selectively inhibited anterograde transport (Fig. 5C; Fig. 6A; p = 0.028), but not retrograde FAT. Surprisingly, aggregated S422E significantly inhibited both anterograde and retrograde FAT rates (Fig. 5D; Fig. 6A, B) compared to S422E monomer (anterograde, p = 0.012; retrograde, p = 0.002) and hT40 aggregates (retrograde only, p = 0.019).

Evidence e3a8093023

Staining in fixed tissue sections confirmed several previous reports (Kanaan et al., 2016; Mufson et al., 2014; Patterson et al., 2011a) that pS422 (Fig. 7A) extensively colocalizes with TNT1 (Fig. 7B) and TOC1 (Fig. 7C) in both control and AD brains, despite the relatively sparse appearance of tau pathology in the temporal cortices of control cases (data not shown).

Evidence 8bef88d987

Highlighting the relevance of these findings to human disease, pS422 tau was found to colocalize with tau oligomers and with a fraction of tau showing increased PAD exposure in the human AD brain. This study identifies novel effects of pS422 on tau biochemical properties, including prolonged nucleation and enhanced dimer formation, which correlate with a distinct inhibitory effect on FAT.


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