Tau Hyperphosphorylation & Tangle Nucleation

Aggregation Drivers

Kinase activity / phosphorylation φ 30%

Tau protein pool N 120

Simulation speed 1.0×

Live State

MT-bound tau

Free monomers

Aggregated (PHF)

Tangle seeds

How it works

Tau normally stabilizes axonal microtubules by binding along their outer surface. Hyperphosphorylation (by kinases such as GSK-3β and CDK5) neutralizes tau's positively charged microtubule-binding repeats, sharply lowering binding affinity and releasing tau into the cytosol as free monomer — the first step toward neurofibrillary tangle formation.

Free tau then aggregates by nucleation-dependent polymerization (Oosawa–Kasai kinetics, as characterized for tau by Friedhoff et al. and Barghorn & Mandelkow): a slow, high-order nucleation step forms a small seed, followed by fast monomer-by-monomer elongation at the fibril ends into paired helical filaments (PHFs).

Detachment:   P(off)  = 1 - exp(-k_off · φ · dt)
Nucleation:   P(nuc)  = k_n · dt · [M_free]^nc      (nc ≈ 2, critical nucleus)
Elongation:   P(add)  = k_e · dt   for M_free within capture radius r_c of a fibril end

φ (phosphorylation) — sets the detachment rate; higher φ empties the microtubule lattice faster, raising the free-monomer pool that fuels aggregation.
Tau pool N — total tau molecules simulated; more tau means more nucleation attempts and denser tangles at the same φ.
Inject Seed Fibril — drops a preformed nucleus directly into the cytosol, modeling prion-like templated seeding, which is known to bypass the slow nucleation step and accelerate tangle growth in real neurons.

Color key: teal spheres are tau still bound to (and stabilizing) the microtubule; amber spheres are free, hyperphosphorylated monomers diffusing in the cytosol; red spheres are tau locked into a growing paired-helical-filament tangle.

MT-bound tau Free monomer Tangle (PHF)

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Tau Hyperphosphorylation & Neurofibrillary Tangle Nucleation