Phospho-Tau (Ser214/T217) Signaling Antibody Sampler Kit

Background

Tau is a heterogeneous microtubule-associated protein that promotes and stabilizes microtubule assembly, especially in axons. Six isoforms with different amino-terminal inserts and different numbers of tandem repeats near the carboxy terminus have been identified, and tau is hyperphosphorylated at approximately 25 sites by Erk, glycogen synthase kinase-3 (GSK-3), and CDK5 (1,2). Phosphorylation decreases the ability of tau to bind to microtubules. Neurofibrillary tangles are a major hallmark of Alzheimer's disease (AD); these tangles are bundles of paired helical filaments (PHFs) composed of hyperphosphorylated tau. Furthermore, research studies have shown that inclusions of tau are found in a number of other neurodegenerative diseases, collectively known as tauopathies (1,3).

Numerous kinases, including p38 MAPK, JNK, CDK5, GSK3β, and SGK1, have been shown to phosphorylate tau at Ser214, which is found in AD and dementia with Lewy bodies (4-9). p38 MAPK participates in a signaling cascade controlling cellular responses to cytokines and stress and is activated by phosphorylation at Thr180 and Tyr182, allowing for downstream tau Ser214 phosphorylation (10-13). Another kinase that phosphorylates the Ser214 site on tau is the stress-activated protein kinase/Jun-amino-terminal kinase (SAPK/JNK). SAPK/JNK is preferentially activated by a variety of environmental stresses, including UV and gamma radiation, ceramides, inflammatory cytokines, and, in some instances, growth factors and GPCR agonists, which lead to phosphorylation of Thr183 and Tyr185 (14-19).

Tau phosphorylation at Thr217 has been identified as a highly specific biomarker of AD. Phosphorylated tau at Thr217 can be detected in cerebrospinal fluid in both preclinical and advanced stages of AD and has been shown to successfully differentiate between AD and non-AD neurodegenerative diseases (20,21). One kinase identified to phosphorylate the Thr217 site on tau is p70 S6 kinase (S6K1). S6K1 is a mitogen activated Ser/Thr protein kinase that is required for cell growth and G1 cell cycle progression (22,23). Phosphorylation of Thr389 most closely correlates with S6K1 activity in vivo (24).