Hyperphosphorylated tau protein (P-tau, pTau, HPT)

Hyperphosphorylated tau protein is a pathological form of the microtubule-associated protein tau that represents a critical hallmark of Alzheimer's disease and other tauopathies. In its normal state, tau contains approximately 30 phosphorylated sites on 79 potential serine and threonine phosphorylation sites. Hyperphosphorylation involves a two- to three-fold increase in phosphate content, reaching approximately 12 moles of phosphate per mole of protein in disease states, with new phosphorylated sites appearing beyond the normal phosphorylation pattern. This excessive phosphorylation causes tau to detach from microtubules, particularly losing its interaction with the β-tubulin subunit more than the α-tubulin subunit. The detachment results from increased flexibility in the microtubule-binding domain and loss of critical salt bridges that normally stabilize the tau-tubulin interaction. The projection domain and proline-rich regions play crucial roles in this process. Upon hyperphosphorylation, tau undergoes conformational changes that enable tau-tau interactions and self-assembly into paired helical filaments and straight filaments, which further aggregate into neurofibrillary tangles. These tangles are approximately 20 nanometers wide, narrowing to 10 nanometers at regular intervals. The protein exists in six isoforms in human brain tissue, distinguished by three or four microtubule-binding domains, and all six isoforms can be found in hyperphosphorylated states in Alzheimer's disease brain tissue. Specific phosphorylation sites have distinct roles: P-Ser262 is critical for tau dissociation from microtubules and appears in preneurofibrillary tangles as an early marker, while combined phosphorylation at Ser262, Ser285, and Ser289 promotes stable dimer formation that contributes to paired helical filament assembly. The hyperphosphorylation is regulated by various kinases and phosphatases, with developmental regulation showing higher phosphorylation in fetal tau that decreases with age through phosphatase activation.

Other names

Hyperphosphorylated microtubule-associated protein tauphosphorylated tauAD P-taupaired helical filaments tautau inclusions

Therapeutic strategies targeting dephosphorylation of hyperphosphorylated tau. Inhibition of kinases (PKN and other tau kinases). Activation of phosphatases (PP2A, PP2B). O-GlcNAc elevation to protect against tau hyperphosphorylation. Prevention of tau self-assembly and aggregation.