| Abstract |
This thesis focuses on the critical function of the p75NTR receptor in a variety of cellular processes, including neurogenesis, neural development, and possible therapeutic applications. Notably, earlier studies have demonstrated the significance of p75NTR in these processes, but this study aims to investigate p75NTR’s neurogenic role both in vivo and in vitro. The choice of the appropriate mouse models was crucial in order to further investigate p75NTR’s function in adult hippocampal neurogenesis and in AD. First, we demonstrated that in 2-month-old mice, p75NTR deletion reduces neural stem cell (NSCs) proliferation while increasing differentiation. These results highlight how crucial function the receptor has in controlling NSCs’ proliferation and differentiation.
Recent research has connected decreased adult hippocampus neurogenesis to the progression of neurodegenerative diseases including Alzheimer's disease (AD). However, our experiments show that NSCs’ proliferation is unexpectedly enhanced in 2-month-old AD mice (5xFAD). This raises the possibility that the central nervous system has a compensating mechanism to encounter neurodegeneration brought on by AD. Importantly, p75NTR deletion in 5xFAD mice reduces NSCs’ proliferation to levels even lower than in wild-type mice, emphasizing the receptor's role in this process. Additionally, the project focuses on the mechanisms that lead to these alterations in proliferation and differentiation of NSCs upon p75NTR’s deletion. A non-autonomous role for p75NTR is suggested by the fact that conditional deletion of p75NTR specifically in neural progenitor cells has no impact on NSCs’ proliferation and differentiation. These findings shed light on the intricate connections that take place between various cell types in the nervous system.
On the other hand, this study describes ENT-A044, a synthetic analog of the natural neurosteroid DHEA, that can activate TrkB and p75NTR receptors, as a possible therapeutic agent. Although DHEA prevents neuronal cell death, its long-term use is problematic because of its hormonal side effects. So, some years ago in our laboratory, a library of synthetic analogs of DHEA that maintain its neurotropic function but lack its undesirable endocrine effects was generated. However, as seen in mouse and human neuronal cultures, the effects of ENT-A044 differ depending on the receptors expressed and the type of neuronal cells. While ENT-A044 triggers cell death predominantly through p75NTR in human NSCs, it decreases cell death in p7 mouse hippocampal NSCs, probably through TrkB activation. This demonstrates how neurotrophin receptor functions vary between species. Based on the above data, ENT-A044 could be used to target cancer cells and lead them to apoptosis through p75NTR-mediated cell death pathways. Lastly, future studies should delve deeper into the function of p75NTR in older mice with severe AD pathology and analyze alterations in gene expression linked to p75NTR signaling by single-cell transcriptomic investigations.
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