Investigating the role of the kinesin motor protein Kif21b in regulating BDNF-TrkB signaling and Tau phosphorylation in Alzheimer`s disease conditions

阿尔茨海默病（AD）的特征在于由淀粉样蛋白β（A β）组成的老年斑的细胞外积累和由过度磷酸化的tau组成的神经元缠结（NFT）的细胞内沉积。“淀粉样蛋白级联假说”强调了Akt积累是导致tau蛋白病的AD的主要致病因素，然而Akt如何诱导Tau过度磷酸化仍然不完全清楚。BDNF水平在AD患者中选择性降低，并且BDNF/TrkB途径在导致Tau磷酸化的信号传导途径的上游起作用。我们以前表明，驱动蛋白马达蛋白Kif 21 b调节神经元中TrkB/BDNF复合物的转运，此外还控制微管生长。有趣的是，Kif 21 b在AD患者中强烈上调。我们的初步数据表明，淀粉样蛋白42在缺乏Kif 21 b的神经元中导致显著更高的细胞毒性。他们进一步表明，在缺乏驱动蛋白马达蛋白的Kif 21 b敲除小鼠的脑裂解物中，Tau磷酸化增加。因此，我们假设Kif 21 b在可能由A毒性诱导的亚细胞途径中起着核心作用，并可能导致tau病理学。在拟议的项目中，我们将询问A是否影响Kif 21 b和/或微管动力学，并旨在了解Kif 21 b调节的BDNF/TrkB复合物的运输和/或其在调节微管生长中的作用是否以及如何参与Tau病理学。我们计划采用细胞方法研究Kif 21 b在BDNF/TrkB下游信号传导中的作用，从而导致Tau磷酸化。此外，我们计划将AD小鼠模型与Kif 21 b敲除小鼠杂交，并将在AD小鼠中病毒过表达Kif 21 b以研究体内后果。了解Kif 21 b和微管动力学在AD病理学背景下的作用可能有助于确定新的靶点，以制定针对该疾病的治疗策略。

Alzheimer’s disease (AD) is characterized by both the extracellular accumulation of senile plaques composed of amyloid beta (Aß) and the intracellular deposition of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. The "amyloid cascade hypothesis" highlights Aß accumulation as the primary causative factor of AD leading to tauopathy, however how Aß induces Tau hyperphosphorylation still remains incompletely understood. BDNF levels are selectively reduced in AD patients and the BDNF/TrkB pathway acts upstream of a signalling pathway leading to Tau phosphorylation. We previously showed that the kinesin motor protein Kif21b regulates the transport of TrkB/BDNF complexes in neurons and in addition controls microtubule growth. Interestingly, Kif21b is strongly upregulated in AD patients. Our preliminary data suggest that amyloid 42 leads to significantly higher cytotoxicity in neurons lacking Kif21b. They further show that Tau phosphorylation is increased in brain lysate from Kif21b knockout mice lacking the kinesin motor protein. We therefore hypothesize that Kif21b plays a central role in subcellular pathways that might be induced by A toxicity and can lead to tau pathology. In the proposed project we will ask whether A affects Kif21b and/or microtubule dynamics and aim to understand whether and how the Kif21b-regulated trafficking of BDNF/TrkB complexes and/or its role in regulating microtubule growth is involved in Tau pathology. We plan a cellular approach to investigate the role of Kif21b in BDNF/TrkB downstream signaling leading to Tau phosphorylation. In addition, we plan to crossbreed an AD mouse model with Kif21b knockout mice and will virally overexpress Kif21b in the AD mice to study in vivo consequences. Understanding the role of Kif21b and microtubule dynamics in the context of AD pathology could help to identify novel targets to develop treatment strategies against the disease.