Kononenko, Natalia - C 08

Late-onset Alzheimer's disease (LOAD) is the most common neurodegenerative disorder characterized by the formation of extracellular amyloid-β (Aβ) plaques and cytoplasmic neurofibrillary tangles (NFTs). Although much has been learnt about Aβ plaques and NFTs, we lack a complete understanding of the cellular pathways that contribute to apoptosis of cells in brain of LOAD patients. Endocytosis is strongly implicated in the pathogenesis of LOAD. Genome-wide association studies (GWAS) have identified several endocytosis-related LOAD-linked risk gene loci, including BIN1, PICALM and lately AP2A1. These genes encode adaptor proteins with the function in clathrin-mediated endocytosis (CME).

How precisely CME contributes to the pathogenesis of LOAD is still under debate. Our laboratory has found that CME components non-canonically regulate brain function and are required for cell cycle progression of neural progenitor cells. This project will therefore specifically focus on understanding the role of LOAD-linked endocytosis risk genes such as AP2A1 in cell cycle control in neuronal cells. Since AP-2 is a crucial CME component, detailed characterization of AP2A1 function in the brain is important for understanding LOAD pathogenesis. 

Strong evidence links neuronal cell loss and cell cycle deregulation in Alzheimer's disease. The underlying mechanism still awaits further clarification. The data from our laboratory suggest that Alzheimer’s disease-associated endocytosis risk factors may prevent neurodegeneration via a novel pathway involving cell cycle control. Using cell biology approaches, transgenic animal models and, AD patient material, we will dissect the molecular pathways governing cell cycle impairments in brains lacking LOAD-linked risk genes. Our study will help develop clinical therapies to combat neuronal cell loss and improve cognitive impairments in LOAD.   

For more information, please check Kononenke Lab. 

• CECAD Cologne
• CMMC Cologne
• Center for Physiology & Pathophysiology, Medical Faculty, University of Cologne
• Institute of Genetics, Math-Nat Faculty, University of Cologne
• CRC 1451