Enhancement of Abeta-induced synaptotoxicity by adhesion protein CTFs in mouse and iPSC-derived human neurons
Molecular Biology and Physiology of Neurons and Glial Cells
Final Report Abstract
This project was based on our previous finding that expression of N-cadherin-CTF1 is able to enhance synaptotoxicity induced by Aβ oligomers in cultured cortical mouse neurons. N-cadherin-CTF1 is a C-terminal fragment resulting from proteolytic processing of N-cadherin by α-secretase (ADAM10), and is further processed by γ-secretase. As the major specific aim of this project, we wanted to learn more about the cellular/molecular mechanisms involved in the enhancement of Aβ-induced synaptotoxicity. We found that expression of N-cadherin-CTF1 as well as inhibition of γsecretase (increasing CTF expression) resulted in a slow down of synaptic vesicle endocytosis. This effect on synaptic function was specific to N-cadherin-CTF1; expression of Neurexin3β-CTF did not exhibit a similar effect. Moreover, we found that a chronic pharmacological slow down of vesicle endocytosis by a low concentration of dynasore resulted in an enhancement of Aβ-induced synaptotoxicity. Because this effect was similar to the enhancement of Aβ-induced synaptotoxicity by N-cadherin-CTF1, it strongly suggests that a slow down of vesicle endocytosis might mechanistically underlie the enhancement of Aβ-synaptotoxicity. As second specific aim, we studied changes in the expression of synaptic adhesion protein CTFs (N-cadherin, Neurexins, Neuroligin1) in AD patients by using Western blot analysis of post-mortem brain samples. It turned out that N-cadherin-CTF1 is specifically elevated, while the other candidates tested were not increased. This indicates that an increased presence of N-cadherin-CTF1 might be relevant for the pathomechanisms of the human disease. As the third specific aim, we studied Aβ-induced synaptotoxicity in cultures of human neurons that were derived from induced pluripotent stem cells (iPSCs). We found that similar mechanisms as described in mouse neurons (loss of AMPA receptors) were induced by Aβ oligomers in human neurons. Moreover, we optimized our human neuron cell culture model for studying Aβ-induced synaptotoxicity in the presence of spontaneous network activity, and will use this optimized human model in future experiments.
Publications
- (2015). Alzheimer's disease-related amyloid-β induces synaptotoxicity in human iPS cellderived neurons. Cell Death Dis. 6:e1709
Nieweg K, Andreyeva A, van Stegen B, Tanriöver G, Gottmann K
(See online at https://doi.org/10.1038/cddis.2015.72) - (2019). Astrocyte lineage cells are essential for functional neuronal differentiation and synapse maturation in human iPSC-derived neural networks. Glia 67:1893-1909
Klapper SD, Garg P, Dagar S, Lenk K, Gottmann K, Nieweg K
(See online at https://doi.org/10.1002/glia.23666) - (2021). Transsynaptic N-Cadherin Adhesion Complexes Control Presynaptic Vesicle and Bulk Endocytosis at Physiological Temperature. Front Cell Neurosci. 15:713693
Dagar S, Teng Z, Gottmann K
(See online at https://doi.org/10.3389/fncel.2021.713693)
