The formation of tau pathological phospho-epitopes in the axon is prevented by the dephosphorylation of selective sites in primary hippocampal neurons over-expressing human tau.

Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montréal, Québec, Canada.
Journal of Neurochemistry (Impact Factor: 4.24). 09/2010; 114(5):1353-67. DOI: 10.1111/j.1471-4159.2010.06855.x
Source: PubMed

ABSTRACT In tauopathies including Alzheimer's disease, the axonal microtubule-associated protein tau becomes hyperphosphorylated at pathological epitopes and accumulates in the somato-dendritic compartment. However, it remains unclear whether tau becomes phosphorylated at these epitopes in the somato-dendritic compartment and/or in the axon. In primary hippocampal neurons where human tau was over-expressed both in the somato-dendritic compartment and the axon, the pathological epitopes recognized by the antibodies AT8 (S199/S202/T205), AT100 (T212/S214/T217), and AT180 (T231/S235) were found in the somato-dendritic compartment but not in the axon where tau was either not phosphorylated (T205 and T217) or not simultaneously phosphorylated (T231 and S235) at sites included in the above epitopes. When transfected neurons were treated with the phosphatase inhibitor, okadaic acid, AT8, AT100 and AT180 epitopes were observed in the axon, indicating that tau was dephosphorylated at selective sites of pathological epitopes in this compartment. Expression of tau mutants where one phosphorylation site included in the above epitopes was mutated in alanine showed that the formation of one of these epitopes was not required for the formation of the two others in primary hippocampal neurons. All together our results indicate that in the somato-dendritic compartment, the kinase and phosphatase activity does not prevent the formation of pathological epitopes whereas in the axon, the amount of tau phosphorylated at the pathological epitopes is regulated by phosphatase activity, most likely that of phosphoserine/phosphothreonine phosphatase 2A, the major tau phosphatase. This indicates that if the pathological epitopes are initially formed in the axon in Alzheimer's disease brain, the activation of phosphatases could be an efficient way to abolish their generation.

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