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- W2897859973 abstract "Tau immunotherapy has recently emerged as a promising approach for the treatment of neurodegeneration. We have previously reported that anti-tau antibody, targeting R1 epitope on tau, inhibited in vitro arachidonic acid-induced aggregation of non-phosphorylated tau. We have also reported the inhibitory role of antibodies to phosphorylated tau on tau protein phosphorylation at Ser199 by GSK-3β. However, the exact mechanism of antibody-based inhibition at the molecular level is still unclear. Antibodies to non-phosphorylated (R4 repeat domain) and to phosphorylated tau (Ab-pSer199, Ab-pThr231, Ab-pSer262, Ab-pSer356) were used for the inhibitory studies. MARK 4-catalyzed phosphorylation of the longest isoform of tau (Tau-441, 2N4R) was evaluated by dot blot and western blot. The aggregation propensity of phosphotau was analyzed by fluorescence spectroscopy and transmission electron microscopy (TEM). Florescence measurements provided information about the hydrophobicity of phosphotau protein and its aggregates. In addition, TEM allowed for morphological analysis of the aggregates formed by phosphotau. The limited proteolysis was carried out with non-phospho and phosphotau proteins in order to compare their stabilities. Phosphorylation level was monitored at Ser199, Thr231, Ser262, and Ser356. MARK 4 phosphorylated Ser262 and Ser356, but not Ser199 and Thr231. The pSer262 and pSer356 levels did not vary in the presence of the antibodies to R4 repeat domain or phospho epitopes. Following phosphorylation, the phosphotau aggregated within hours as evidenced by TEM. The aggregation was reduced by antibodies to R4 repeat domain or to pSer262. Notably, the non-phospho and phosphotau were degraded by trypsin to a similar extent. Antibodies did not modulate pSer262 and pS356 levels, but the phosphotau generated by MARK 4 was prone to aggregation. The antibodies targeting R4 domain or pSer262 site reduced aggregation and are promising inhibitory antibodies. Further studies will be carried on the antibodies efficacy in isoform-specific manner using all six tau isoforms." @default.
- W2897859973 created "2018-10-26" @default.
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- W2897859973 date "2018-07-01" @default.
- W2897859973 modified "2023-10-16" @default.
- W2897859973 title "P4‐221: ROLE OF ANTI‐TAU ANTIBODIES ON TAU‐441 PHOSPHORYLATION BY MARK 4, AND ITS AGGREGATION" @default.
- W2897859973 doi "https://doi.org/10.1016/j.jalz.2018.07.042" @default.
- W2897859973 hasPublicationYear "2018" @default.
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