Tau phosphatase activity as a therapeutic target for AD.

In the normal brain, tau promotes the assembly of tubulin into microtubules and maintains the structure of microtubules, which are required for axonal transport. Tau in AD brain is abnormally hyperphosphorylated ("AD P-tau") and does not promote the in vitro assembly of microtubules, bind to microtubules or stabilize their structure. Employing phosphorylation-dependent antibodies to tau, site-specific dephosphorylation of AD P-tau has been investigated. The phos-phoseryl/phosphothreonyl protein phosphatases (PSPs) PP-1, PP-2A and PP-2B rapidly dephosphorylated AD P-tau in vitro. The dephosphorylation of neurofibrillary tangles of paired helical filaments by the two major tau phosphatases, PP-2A and PP-2B, has been demonstrated to produce marked biochemical, biological and structural alterations. Thus, by increasing the activity of one more of these tau phosphatases, it might be possible to prevent and inhibit neuronal degeneration and consequently both the sporadic and the familial forms of AD. (c) 1998 Prous Science. All rights reserved.