Microtubule‐associated Protein Tau, Paired Helical Filaments, and Phosphorylation^a

Abstract

This paper summarizes our recent studies on microtubule-associated protein tau and its pathological state resembling that of the paired helical filaments of Alzheimer's disease. The Alzheimer-like state of tau protein can be identified and analyzed in terms of certain phosphorylation sites and phosphorylation-dependent antibody epitopes. It can be induced by protein kinases which tend to phosphorylate serine or threonine residues followed by a proline; this includes mitogen-activated protein kinase (MAPK) and glycogen-synthase kinase 3 (GSK-3). Both of these are tightly associated with microtubules as well as with paired helical filaments. Structurally, tau appears as a rod-like molecule; it tends to self-associate into dimers whose monomers are antiparallel. Constructs of truncated tau made up of antiparallel dimers of the microtubule binding domain can be assembled into paired helical filaments in vitro.

RETRACTED ARTICLE: Fuzhisan, a Chinese Herbal Medicine, Inhibits Beta-Amyloid-Induced Neurotoxicity and Tau Phosphorylation Through Calpain/Cdk5 Pathway in Cultured Cortical Neurons

“…Interestingly, the neuroprotective effect of FZS is superior to that of roscovitine or calpeptin. It is most likely that FZS is a herbal medicine that contains multiple components, and we consider that in addition to the inhibition of Cdk5 activity, other tau kinase such as GSK3b may also be involved [11]. However, this will be further explored in future studies.…”

“…Given the evidence that Ab requires tau proteins to induce its neurotoxicity [9], and tau phosphorylation is a limiting factor in Ab-induced cell death [10], it is reasonable to speculate that Ab-induced tau phosphorylation may be an important pathogenesis of AD [4]. Earlier studies have indicated that Ab-induced tau phosphorylation is mediated by the activation of various kinases including glycogen synthase kinase 3 beta (GSK3b), mitogen-activated protein (MAP) kinase, and cyclin-dependent kinase 5 (Cdk5) [11][12][13][14]. Of these kinases, Cdk5 has been found to phosphorylate tau at AD-specific phospho-epitopes and its activity is enhanced in response to Ab in cultured neurons [13,15,16].…”

FRAT-2 Preferentially Increases Glycogen Synthase Kinase 3β-mediated Phosphorylation of Primed Sites, Which Results in Enhanced Tau Phosphorylation

“…Recombinant tau is a good substrate for GSK3␤ in vitro (21,38,39) and is unprimed. When GSK3␤ was immunoprecipitated from cell lysates that were transfected with GSK3␤ and FRAT-2 with a monoclonal HA antibody, it phosphorylated the recombinant tau to the same extent as the GSK3␤ immunoprecipitated from cells expressing just GSK3␤ (Fig.…”

Axin negatively affects tau phosphorylation by glycogen synthase kinase 3β

“…Tau is an excellent substrate for GSK3b (Mandelkow et al 1993;Lovestone et al 1994;Wagner et al 1996). To further examine the effects of axin on GSK3b-mediated tau phosphorylation, HEK cells were transfected as above and GSK3b was immunoprecipitated from the lysates and used to [ 32 P]phosphorylate recombinant tau, in an in vitro assay (Fig.…”