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

研究驱动蛋白运动蛋白 Kif21b 在阿尔茨海默病中调节 BDNF-TrkB 信号传导和 Tau 磷酸化的作用

• 批准号: 531045197
• 负责人: Professor Dr. Matthias Kneussel, Ph.D.
• 金额: --
• 依托单位: Zentrum für Molekulare Neurobiologie (ZMNH)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/531045197?language=en
• 关键词: Investigating; role; kinesin; motor; protein

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.

阿尔茨海默病(AD)的特点是细胞外聚集由淀粉样β蛋白(A？)组成的老年斑和细胞内沉积由过度磷酸化tau组成的神经原纤维缠结(NFT)。“淀粉样蛋白级联假说”强调A？堆积是导致AD的主要致病因素，然而A？如何诱导Tau过度磷酸化仍不完全清楚。AD患者BDNF水平选择性降低，BDNF/TrkB通路作用于导致Tau磷酸化的信号通路的上游。我们之前已经证明，Kinesin马达蛋白Kif21b调节神经元中TrkB/BDNF复合体的运输，此外还控制微管的生长。有趣的是，Kif21b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Kif21b的神经元中导致显著更高的细胞毒性。他们进一步表明，在Kif21b基因敲除小鼠中，缺乏Kinesin马达蛋白的脑裂解物中Tau的磷酸化水平增加。因此，我们假设Kif21b在A毒性可能诱导的亚细胞通路中发挥核心作用，并可能导致tau病理。在拟议的项目中，我们将询问A是否影响Kif21b和/或微管动力学，并旨在了解Kif21b是否以及如何调节BDNF/TrkB复合体的运输和/或其在调节微管生长中的作用参与Tau病理。我们计划用细胞方法研究Kif21b在导致Tau磷酸化的BDNF/TrkB下游信号中的作用。此外，我们计划将Kif21b基因敲除小鼠与AD小鼠模型杂交，并在AD小鼠中以病毒方式过表达Kif21b，以研究体内后果。了解Kif21b和微管动力学在AD病理中的作用有助于确定新的靶点，以开发针对该疾病的治疗策略。