Fig. 9.

Schematic diagram of Aβ and TTBK1-induced phosphorylation of CRMP2 and tau, neurite degeneration and their accumulation in neuronal cell soma. a In healthy neurons, kinesin-1-mediated anterograde transport is dominant (green arrow) over dynein-mediated retrograde transport (red arrow) for transporting α/β-tubulin dimer for axonal extension. b Upon stimulation with Aβ or activation of protein kinases by TTBK1, CRMP2 is phosphorylated by Cdk5, GSK3β and RhoK (pCRMP2, yellow), and dissociates from kinesin-1, leading to more retrograde-dominant transport (red arrow) over their anterograde transport (green arrow). The loss of supply of α/β-tubulin by CRMP2 to the microtubule tip leads to depolymerization of neurite terminal, inducing dissociation of tau (green). Dissociated tau is phosphorylated by tau kinases (pTau, yellow), which binds to pCRMP2 and concentrates in the cell soma via retrograde transport. The pCRMP2/pTau complex was found in EC neurons in TTBK1 mice. Accumulation of Aβ may accelerate this process and promote pCRMP2 accumulation in not only EC but also DG neurons in APP/TTBK1 mice