Modulatory Role of Anti‐Tau Antibodies on Phosphorylation of Tau‐441 by MARK4

Abstract

Tau protein stabilizes microtubules in neurons. The detachment of tau from microtubules, induced by post‐translational modifications, leads to tau aggregation, neuronal cell death, and cytotoxicity. The hyperphosphorylation of tau is one of the main causes of tau pathology in neurodegeneration. The current immunotherapies that target tau protein have shown clearance of tau pathology in animal models. However, it is still unclear how antibody‐based inhibition of tauopathies takes place. We have shown that anti‐tau antibody, targeting R1 epitope of tau, inhibited in vitro aggregation of non‐phosphorylated tau‐441. We also reported that phosphorylation of tau‐441 at S199 may be inhibited by antibodies to phosphorylated tau. Here, we report on the effects of anti‐tau antibodies to non‐phosphorylated tau (epitope at R4 repeat domain) on the phosphorylation outcomes of tau‐441 when MARK4 was used as a protein kinase. Using Dot blots and Western blots we evaluated the phosphorylation at S199, T231 and S262 residues of tau‐441. MARK4‐catalyzed phosphorylation of tau‐441 indicated a successful phosphorylation at S262 and S199, but not at T231. However, in the presence of anti‐tau antibodies (binding to tau R4 epitope) the phosphorylation at T231 was turned on, while phosphorylation at S199 and S262 remained unchanged. These findings suggest that phosphorylation of tau at specific sites may be modulated by using antibodies specific tau epitopes.Support or Funding InformationNIH/NIGMS R15 GM11905301