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

• Applicant: Professor Matthias Kneussel, Ph.D.
• Subject Area: Experimental Models for the Understanding of Nervous System Diseases
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531045197

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.

• DFG Programme: Research Grants