Increase in tau tyrosine phosphorylation correlates with the formation of tau aggregates

Abstract

Tauopathies are neurodegenerative disorders characterized by aberrant intracellular aggregation of hyperphosphorylated tau. It has been shown that aggregated tau is phosphorylated at serine, threonine, and tyrosine residues. However, the occurrence of tyrosine phosphorylation on tau proteins at different states of tau aggregation has not been shown. In this report, we utilized the tauopathy mouse model JNPL3 that expresses human 0N4R tau isoform bearing the missense P301L mutation to study the occurrence of tau tyrosine phosphorylation in the course of the development of tau aggregation. These mice develop behavioral and motor deficits and form sarkosyl-insoluble hyperphosphorylated tau in an age-dependent manner. Mass spectrometry analyses of immunopurified brain tau proteins from JNPL3 and Alzheimer's disease affected individual uncovered novel tau tyrosine-phosphorylated sites. Further studies demonstrated that the abundance of tyrosine-phosphorylated tau increases in an age-dependent manner in JNPL3 mice. Tyrosine-phosphorylated tau was detected in both soluble and sarkosyl-insoluble preparations derived from brain and spinal cord, and localized in neurons containing aggregated tau. The phosphorylation of tyrosine residues in tau appeared to occur along with that of serine and threonine residues and was not detectable in non-transgenic littermates and transgenic mice expressing 0N4R wild-type human tau. The results suggest that tyrosine phosphorylation is as important as phosphorylation of other residues in tauopathy.

Early Axonopathy Preceding Neurofibrillary Tangles in Mutant Tau Transgenic Mice

“…In agreement with another study, 54 we detected phosphotyrosine immunoreactivity in NFTs, suggesting that the mutant tau protein was phosphorylated on tyrosine amino acid residues. Tyrosine phosphorylation of tau has been reported in AD brain, 55,56 and A␤ was found to induce tyrosine phosphorylation of tau, 57 but the present finding indicates that tyrosine phosphorylation of tau can also occur in the absence of A␤.…”

Exosome-associated Tau Is Secreted in Tauopathy Models and Is Selectively Phosphorylated in Cerebrospinal Fluid in Early Alzheimer Disease

“…This difficulty, plus the lack of any secretion-associated motifs on tau, has fostered the assumption that tau secretion only occurs in association with nonphysiological tau overexpression and is thus irrelevant to tau pathobiology. However, recent demonstrations of high efficacy and specificity of tau secretion, toxicity, uptake, and interneuronal transfer in various tauopathy models (1)(2)(3)(4)(5)(6) and that these events and characteristics are modulated by disease-relevant tau alterations such as phosphorylation (3,(27)(28)(29)(30)(31), cleavage (34,38), and oligomerization (26,37,46,47) suggest that secretion may play a significant role in tau-associated neurodegeneration. The involvement of tau secretion in the genesis of increased CSF tau levels in the earliest stages of AD may therefore mark a significant change in our overall view of AD pathogenesis, both because of the new insights that it provides into disease-associated mechanisms of tau misprocessing and because of the potential clinical importance of tau secretion biomarkers for CSF-based AD diagnostics.…”

“…30, 31). These proteins included the nonreceptor tyrosine kinase fyn (27,28) and ␤-amyloid peptide 1-42 (29).…”

Curcumin Suppresses Soluble Tau Dimers and Corrects Molecular Chaperone, Synaptic, and Behavioral Deficits in Aged Human Tau Transgenic Mice

“…For example, NR2B translocation and retention in the PSD NMDA receptor complex (35) is regulated by Fyn, a kinase that binds, travels with, and phosphorylates Tau at Tyr-18. Because Fyn is lost from synaptic sites and co-localizes with NFTs in clinical AD (47) and AD models (48), this suggests Tau aggregation does not compromise Fyn binding but instead mislocalizes Fyn to aggregates (NFT). The hTau transgene resulted in elevations in Fyn in SDS fractions enriched in insoluble Tau, consistent with Fyn involvement in AD tauopathy.…”