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
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
复制标题
DOI：
10.1186/s40478-020-0890-4
复制
发表时间：
2020-02-04
影响因子：
7.1
通讯作者：
Ikezu, Tsuneya
中科院分区：
文献类型：
--
作者：
Ikezu, Seiko;Ingraham Dixie, Kaitlin L.;Ikezu, Tsuneya
磷酸化tau蛋白（pTau）在内嗅皮层（EC）中的积累是阿尔茨海默病（AD）中最早的tau病理学。Tau微管蛋白激酶-1（TTBK 1）是一种神经元特异性的tau激酶，在人和小鼠脑的EC和海马区域中表达。在这里，我们报告说，生长锥崩溃的关键介质，生长素反应介质蛋白-2（CRMP 2），是一个新的下游目标TTBK 1和积累在早期AD大脑的EC区域。TTBK 1转基因小鼠在穿通通路中显示出严重的轴突变性，其通过与表达淀粉样前体蛋白（APP）的瑞典家族性AD突变体的Tg 2576小鼠杂交而加剧。TTBK 1小鼠在10个月龄时在EC中显示磷酸化CRMP 2（pCRMP 2）的积累，而年龄匹配的APP/TTBK 1双基因小鼠在EC和海马区均显示pCRMP 2积累。淀粉样β肽（A β）和TTBK 1抑制微管聚合动力学，TTBK 1以Rho激酶依赖的方式减少体外原代培养神经元的轴突长度。TTBK 1的沉默或显性负性Rho激酶的表达表明，在体外，A β以TTBK 1依赖的方式诱导CRMP 2在苏氨酸514处的磷酸化，并且TTBK 1以Rho激酶依赖的方式增强A β诱导的CRMP 2磷酸化。此外，TTBK 1表达在体外诱导pCRMP 2与pTau的复合物形成，其在体外A β刺激后增强。最后，pCRMP 2在体内与TTBK 1小鼠的EC组织中的pTau形成复合物，其在APP/TTBK 1小鼠的EC和海马组织中均加剧。这些结果表明，TTBK 1和A β诱导CRMP 2磷酸化，这可能是EC神经元中神经突变性和pTau体积累的原因，表明TTBK 1和pCRMP 2在早期AD病理学中的关键参与。
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-beta peptide (A beta) and TTBK1 suppress 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 A beta induces CRMP2 phosphorylation at threonine 514 in a TTBK1-dependent manner, and TTBK1 enhances A beta-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 A beta 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 A beta 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.