Dephosphorylation of tau protein and Alzheimer paired helical filaments by calcmeurin and phosphatase‐2A

Abstract

We have shown previously that brain tissue contains protein kinases which can phosphorylate tau protein to a state reminiscent of the pathological state of Alzheimer paired helical filaments (PHFs); these include proline-directed kinases which phosphorylate SP or TP motifs (such as MAP kinase and GSK-3) ; Mandelkow et al. (1992)], as well as a novel kinase which phosphorylates S262 of tau protein and thereby strongly reduces the binding of tau to microtubules [Biemat et al. (1993)]. Here we report on the corresponding phosphatases in brain which normally keep the 'pathological' sites free of phosphate. The major phosphatases acting on tau are calcineurin and PP-2A, but not PP-1. Both are present and active in brain extracts, they can dephosphorylate recombinant tau after prior phosphorylation with either MAP kinase, GSK-3, or brain extract, and the course of dephosphorylation can be monitored with antibodies diagnostic of the pathological state of tau. Both phosphatases also act directly on PHF tau isolated from Alzheimer brains.

Phosphorylation of Microtubule-associated Protein Tau Is Regulated by Protein Phosphatase 2A in Mammalian Brain

“…By using the abnormally hyperphosphorylated tau isolated from AD brain as a substrate, we have previously found that PP2A, PP2B, and, to a less extent, PP1 but not PP2C can efficiently dephosphorylate tau in vitro (12,(22)(23)(24). Similar findings have also been reported by using 32 P-labeled tau with various protein kinases as a substrate in vitro (25)(26)(27) or using in vivo phosphorylated tau as a substrate (27)(28)(29)(30). However, to date it is not known which of these three phosphatases regulates tau phosphorylation in vivo and by what mechanism tau is abnormally hyperphosphorylated in AD brain.…”

“…Slices-In vitro studies have suggested that PP2A and PP2B are the best candidate phosphatases involved in the regulation of the phosphorylation of tau (12,(22)(23)(24)(25)(26)(27)(28)(29)(30). Hence, we examined the phosphorylation of tau in these brain tissue slices when either PP2A or PP2B was selectively inhibited.…”

Abnormal Alzheimer‐like phosphorylation of tau‐protein by cyclin‐dependent kinases cdk2 and cdk5

“…and the corresponding phosphatases in the genesis of AD remains to be established. As shown elsewhere [51], both calcineurin and phosphatase-2A can clear the sites affected by the kinases mentioned above. It may be significant that the three proline-directed kinases can be purified as microtubule-associated proteins and are present in neurofibrillary tangles, suggesting that MAPS act as anchors for the kinases and thus are potential targets for them.…”

PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments

“…Analyses conducted on postmortem AD brains have found reduced PP2A expression and activity, and studies conducted in animal models have found that inhibiting PP2A produces AD-like tau pathology and cognitive impairment (1)(2)(3). One of the ways in which PP2A may affect AD is through its role as the principal tau phosphatase (4)(5)(6)(7). PP2A also interacts with a number of kinases implicated in AD including glycogen synthase kinase 3β (GSK3β), cyclindependent kinase 5 (CDK5), and ERK and JNK as well as amyloid precursor protein and the NMDA and metabotropic glutamate receptors (reviewed in ref.…”