NEURONAL KINASE STIMULATION LEADS TO ABERRANT TAU PHOSPHORYLATION ANDNEUROTOXICITY

Neurofibrillary tangles in Alzheimer's disease brain consist mainly of abnormally phosphorylated tau proteins organised in paired helical fi laments. Induction of tan phosphorylation in living neurons by hyperst imulation is monitored by specific monoclonal antibodies, such as AT-8 and PHF-1. By quantitative immunocytochemistry, we show that aberrant phosphorylation at the Ser199/Ser202 epitope (AT-8) and at the Ser 39 6 epitope (PHF-1) are moderately induced, proportionally to the degree of kinase stimulation. Whereas AT8 expression is prominent after 48 h , cell death becomes significant at 72 h and is related to the degree of stimulation and the expression level of aberrant tau phosphorylatio n. Time-lapse videomicroscopy of individual neuroblastoma cells sugges t that hyperstimulation leads to a form of morphological over-differen tiation. Immediately before cell death, some cells tend to display som e features of mitosis. The data suggest a strong correlation between t he expression of specific PHF-epitopes and subsequent cell death. The extended time scale of toxicity in this model may be appropriate to st udy in more detail the steps leading to aberrant phosphorylation assoc iated neurotoxicity.