TAU CLEAVAGE AND DEPHOSPHORYLATION IN CEREBELLAR GRANULE NEURONS UNDERGOING APOPTOSIS

Cerebellar granule cells undergo apoptosis in culture after deprivatio n of potassium and serum. During this process we found that tau, a neu ronal microtubule-associated protein that plays a key role in the main tenance of neuronal architecture, and the pathology of which correlate s with intellectual decline in Alzheimer's disease, is cleaved. The fi nal product of this cleavage is a soluble dephosphorylated tau fragmen t of 17 kDa that is unable to associate with microtubules and accumula tes in the perikarya of dying cells. The appearance of this 17 kDa fra gment is inhibited by both caspase and calpain inhibitors, suggesting that tau is an in vivo substrate for both of these proteases during ap optosis. Tau cleavage is correlated with disruption of the microtubule network, and experiments with colchicine and taxol show that this is likely to be a cause and not a consequence of tau cleavage. These data indicate that tau cleavage and change in phosphorylation are importan t early factors in the failure of the microtubule network that occurs during neuronal apoptosis. Furthermore, this study introduces new insi ghts into the mechanism(s) that generate the truncated forms of tau pr esent in Alzheimer's disease.