E) and DAPK-/- mice brain displays a decreased phosphorylation of tau [123].Int. J. Mol. Sci. 2014, 15 four.1.1.eight. PKACyclic AMP (cAMP)-dependent protein kinase (PKA) can be a serine/threonine protein kinase which belongs for the non-PDPK class. PKA catalyzes tau phosphorylation in vitro and in vivo [12426]. The phosphorylation of tau protein by PKA triggers subsequent tau phosphorylation by GSK-3 at numerous AD-relevant phosphorylation web sites (Thr181, Ser199, Ser202, Thr205, Thr217, Thr231, Ser396 and Ser422) and simultaneously inhibits tau phosphorylation at Thr212 and Ser404. Moreover, prephosphorylation of tau by PKA slightly promotes tau phosphorylation by cdk5 kinase at Ser396 and inhibits its phosphorylation at Ser202, Thr212, Thr217 and Ser404 [123]. Abnormal phosphorylation from the tau protein by PKA kinase was confirmed in vivo [127]. It has been also observed that infusion of PKA activator, forskolin, into the lateral ventricle of brain in adult rats induced activation of PKA by numerous fold and concurrently enhanced the phosphorylation of tau. four.1.1.9. TPKI and TPKII Tau protein kinase I (TPKI) can be a non-PDPK which will phosphorylate native tau isolated from normal brain, that is already phosphorylated to some extent, but it can not phosphorylate completely dephosphorylated tau. In contrast, TPKII can phosphorylate also the latter kind of tau [128]. The tau residues phosphorylated by TPKII have been Ser202, Thr205, Ser235, and Ser404, although these by TPKI had been Ser199, Thr231, Ser396, and Ser413 [129].Antiflammin 2 Interestingly, the TPKII-dependent tau phosphorylation enhanced with rising A concentration [130]. Related interaction has been postulated within the case of TPKI [131]. 4.1.2. Tau Phosphatases Protein phosphatases (PPs), accountable for dephosphorylation of tau incorporate: PP2B, PP2A, PP1 and PP5 [132]. 4.1.2.1. PP2B Protein phosphatase PP2B (calcineurin) is among the major serine/threonine phosphatases in the brain the activity of which is determined by Ca2+/calmodulin.Difluprednate It consists of a catalytic A subunit with molecular mass of about 63 kDa as well as a regulatory B subunit with molecular mass of about of 19 kDa, which binds Ca2+ and shares some degree of homology with calmodulin.PMID:23892407 The outcomes obtained applying phosphorylation-sensitive monoclonal antibodies AT-180 (against tau phosphorylated on Thr231) and AT-270 (for Thr181) show that reduction of PP2B activity in brain by antisense oligonucleotides led to persistent phosphorylation of tau at Thr181 and Thr231 [133]. Studies performed by Rahman et al. [134] showed that PP2B purified from AD brains effectively dephosphorylated p-tau. The authors found also that the purified PP2B dephosphorylated tau obtained from AD brain at Ser199, Thr217, Ser262, Ser396 and Ser422 together with the preferential dephosphorylation at Ser262 and Ser396. Interestingly, no significant difference in PP2B activity was found between control and AD brain in contrast towards the results obtained by Qian et al. [135] who showed a 3-fold raise in PP2B activity in AD brain as when compared with manage one particular. The study of Kim et al. [136] concerning the PP2B phosphatase revealed that it might catalyze dephosphorylation on the Ser9 residue on GSK-3. The overexpression of aInt. J. Mol. Sci. 2014,constitutively active PP2B mutant (A beta 101) enhanced GSK-3 activity and in consequence phosphorylation of tau. As a result, PP2B similarly to other phosphatases could also act indirectly on tau phosphorylation. 4.1.two.two. PP2A Protein phosphatase 2A (PP2A) is often a main brain.
