Impact of astrocytes on Amyloid precursor protein synaptic function

• Applicants: Professor Dr. Jochen W. Herms; Professor Dr. Stefan Kins
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497637663

In addition to its central role in Alzheimer's pathogenesis the Amyloid precursor protein (APP) has an important function at the synapse. We and others have been able to show that a loss of APP affects synaptic transmission. This has been primarily attributed to the loss of APP expression in neurons. However, we have shown that loss of APP also affects astrocyte function and that it affects the function of excitatory synases. Furthermore, we have recently reported that astrocytes lacking APP show reduced Ca2+ transients, which is probably caused by altered mitochondrial function. We were able to confirm this finding in cell culture analyses, which now allows us to investigate the underlying molecular mechanisms. Furthermore, our preliminary results show that a synaptogenic factor secreted by astrocytes promotes trans-directional dimerization of APP. Since APP trans-dimerization is important for the synaptic function of APP in addition to the action of sAPP, it seems likely that APP and the newly identified synaptogenic factor function in an interdependent manner. In this project proposal, we aim to (A) further analyze the effects and underlying molecular mechanisms of APP loss of function in astrocytes. Furthermore, we would like to (B) investigate the consequences of APP loss of function in astrocytes on the structural synaptic plasticity of synaptic spines in GFP-labeled cortical neurons in vivo. Finally, we would like to investigate (C) the functional interplay of APP and the newly identified astrocyte-secreted synaptogenic factor, which we have shown to enhance APP trans-dimerization, at the synapse in cell culture and in vivo. Using these different approaches we consider on the one hand the function of APP in astrocytes (A+B) and on the other hand the influence of astrocytic secreted proteins on the synaptic function of APP (C).In summary, these studies will contribute to a more comprehensive understanding of the function of APP at the synapse (consisting of neurons and astrocytes). In addition, we expect these studies to provide important insights into possible side effects of therapeutic interventions that potentially affect in particular the physiological function of APP in astrocytes.

• DFG Programme: Research Grants