Proteasome inhibition increases tau accumulation independent of phosphorylation

An intrinsic link between proteasome and tau degradation in Alzheimer's disease (AD) hits been suggested, however, the role of proteasome in the proteolysis of tau is still uncertain. Here, we investigated the influence of proteasome inhibition oil the accumulation, phosphorylation, ubiquitination, solubility of tau and the memory retention in rats. We observed that lactacystin inhibited the proteasome activities and increased the level and insolubility of different tau species, including phosphorylated tau. The elevation of the phosphorylated tau W;Is no longer present and the level of pS214 and pT231 tau was even lower than normal level after normalized to total tau Inhibition of proteasome resulted in activation of cAMP-dependent protein kinase, glycogen synthase kinases-3 beta and cyclin-dependent kinase-5, and inhibition of protein phosphatase-2A and c-Jun N-terminal kinase (JNK) Proteasome inhibition did not affect the memory retention of the rate We conclude that proteasome inhibition increases accumulation and insolubility of tau proteins independent of tau phosphorylation, and JNK inhibition may be partially responsible for the relatively decreased phosphorylation of tau in the rat brains. (C) 2008 Elsevier Inc All rights reserved