Tau-tubulin kinase 1 and amyloid-β peptide induce phosphorylation of collapsin response mediator protein-2 and enhance neurite degeneration in Alzheimer disease mouse models

Abstract

The accumulation of phosphorylated tau protein (pTau) in the entorhinal cortex (EC) is the earliest tau pathology in Alzheimer's disease (AD). Tau tubulin kinase-1 (TTBK1) is a neuron-specific tau kinase and expressed in the EC and hippocampal regions in both human and mouse brains. Here we report that collapsin response mediator protein-2 (CRMP2), a critical mediator of growth cone collapse, is a new downstream target of TTBK1 and is accumulated in the EC region of early stage AD brains. TTBK1 transgenic mice show severe axonal degeneration in the perforant path, which is exacerbated by crossing with Tg2576 mice expressing Swedish familial AD mutant of amyloid precursor protein (APP). TTBK1 mice show accumulation of phosphorylated CRMP2 (pCRMP2), in the EC at 10 months of age, whereas age-matched APP/TTBK1 bigenic mice show pCRMP2 accumulation in both the EC and hippocampal regions. Amyloid-β peptide (Aβ) and TTBK1 suppresses the kinetics of microtubule polymerization and TTBK1 reduces the neurite length of primary cultured neurons in Rho kinase-dependent manner in vitro. Silencing of TTBK1 or expression of dominant-negative Rho kinase demonstrates that Aβ induces CRMP2 phosphorylation at threonine 514 in a TTBK1-dependent manner, and TTBK1 enhances Aβ-induced CRMP2 phosphorylation in Rho kinase-dependent manner in vitro. Furthermore, TTBK1 expression induces pCRMP2 complex formation with pTau in vitro, which is enhanced upon Aβ stimulation in vitro. Finally, pCRMP2 forms a complex with pTau in the EC tissue of TTBK1 mice in vivo, which is exacerbated in both the EC and hippocampal tissues in APP/TTBK1 mice. These results suggest that TTBK1 and Aβ synergistically induce phosphorylation of CRMP2, which may be causative for the neurite degeneration and somal accumulation of pTau in the EC neurons, indicating critical involvement of TTBK1 and pCRMP2 in the early AD pathology.This work was funded in part by NIH

Tau tubulin kinase 1 and 2 regulate ciliogenesis and human pluripotent stem cells–derived neural rosettes

“…In addition, primary cilia are emerging as critical regulators of CNS functionality (Bowie & Goetz, 2020; Schmidt et al , 2022; Sheu et al , 2022). Given that TTBK1 has been considered a plausible therapeutic target for the treatment of Alzheimer’s disease (AD) (Ikezu et al , 2020; Halkina et al , 2021; Nozal & Martinez, 2019; Taylor et al , 2018), its direct involvement in primary cilia regulation may significantly hamper these efforts in AD targeting. Therefore, future studies should address in which cell types is TTBK1 able to regulate ciliogenesis and the exact mechanism of its action.…”

Modulation of Tau Tubulin Kinases (TTBK1 and TTBK2) Impacts Ciliogenesis

“…Expression of TTBK1 is localized to the brain, especially in the cytoplasm of cortical, hippocampal, and entorhinal cortex neurons, and overexpressed in neurodegenerative diseases (Ikezu et al, 2020; Nozal and Martinez, 2019; Sato et al, 2006). Although TTBK2 is ubiquitously expressed in human tissues, higher expression has been reported in the cerebellum Purkinje cells, granular cell layer, hippocampus, midbrain, and substantia nigra (Houlden et al, 2007).…”

“…These same epitopes are also hyperphosphorylated in neurofibrillary tangles (NFT), a key pathological hallmark in several neurodegenerative diseases, including AD (Sato et al ., 2006). Furthermore, TTBK1 expression induces neurite and axonal degeneration, indicating other critical functions for this kinase in early AD pathology (Ikezu and Ikezu, 2014; Ikezu et al ., 2020). In addition to these roles in early AD, TTBK1 is upregulated in the frontal cortex of AD patients and single nucleotide polymorphisms (SNPs) in the TTBK1 gene are associated with late-onset AD (LOAD) (Sato et al, 2008; Yu et al, 2011).…”

Discovery of Potent and Brain-Penetrant Tau Tubulin Kinase 1 (TTBK1) Inhibitors that Lower Tau Phosphorylation In Vivo

“…Tau tubulin kinase 1 (TTBK1) is a kinase that is specifically expressed in the CNS 1,2 and has been reported to phosphorylate tau at a number of disease-related epitopes. 3,4 Hyperphosphorylated tau, which aggregates in the form of neurofibrillary tangles (NFTs), is a key pathological hallmark in a number of neurodegenerative diseases, including Alzheimer's disease (AD), 5,6 and is thought to play a significant role in the progression of disease.…”