Tau pathology in Alzheimer's disease (AD) includes hyperphosphorylation and truncation of tau. Phosphorylation at 5422 is found to suppress truncation of tau at D421 that leading to the generation of Delta Tau. However, the interrelation between hyperphosphorylation and generation of Delta Tau in AD remains elusive. In current study, staurosporine (Stau) induced Delta Tau generation by caspases in SH-SY5Y cells with tau over expression was found to be accompanied by a dramatic dephosphorylation at 5422 and the epitope of the diagnostic antibody AT8 (S199 + S202 + T205), but a moderate dephosphorylation of PHF1 (S396 + S404) epitope. Therefore, to explore the effect of AT8 epitope on tau truncation, the residues in AT8 epitope were mutated to produce "pseudo-phosphorylated" (AT8E) or "pseudo-unphosphorylated" (AT8A) tau constructs. With Stau treatment, the generation of Delta Tau from tau-AT8E was significantly attenuated comparing with that from tau-AT8A, which was S422-independent in that addition of S422A mutation still preserved this effect. Interestingly, this modulatory effect was able to be reversed by addition of PHF1E mutation. Moreover, treating the crude tau extracts with recombinant caspase-3 in vitro, also showed that ATau level was suppressed by AT8E, and potentiated by AT8E + PHF1E. The results primarily revealed the modulating effects of phosphorylation on Delta Tau generation which may have potential implications in tau pathological processes and therapeutic intervention.
[1]Fudan Univ, Shanghai Med Coll, State Key Lab Med Neurobiol, 131 Dongan Rd, Shanghai 200032, Peoples R China;
[2]Fudan Univ, Shanghai Med Coll, Inst Brain Sci, 131 Dongan Rd, Shanghai 200032, Peoples R China;
[3]Shanghai Jiao Tong Univ, Renji Hosp, Sch Med, Dept Neurol, Shanghai, Peoples R China
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