Your browser does not support JavaScript!

Home    Collections    Type of Work    Doctoral theses  

Doctoral theses

Current Record: 5 of 2409

Back to Results Previous page
Next page
Add to Basket
[Add to Basket]
Identifier 000460426
Title Deciphering the role of the p75 pan-neurotrophin receptor in adult hippocampal eurogenesis as a novel therapeutic approach to Alzheimer's Disease
Alternative Title Προσδιορισμός του ρόλου του παν-νευροτροφικού υποδοχέα p 75 στην ενήλικη νευρογένεση του ιπποκάμπου, ως νέα θεραπευτική προσέγγιση στη νόσο Αλζχάιμερ
Author Παπαδοπούλου, Μαρία ¨Αννα
Thesis advisor Χαραλαμπόπουλος, Ιωάννης
Reviewer Γραβάνης, Αχιλλέας
Ζαγανάς, Ιωάννης
Θερμού, Κυριακή
Καραγωγέως, Δόμνα
Βιδάκη, Μαρίνα
Σιδηροπουλου, Κυριακή
Abstract The pan-neurotrophin p75 receptor (p75NTR) is a member of the TNF death receptor superfamily, being widely expressed in many cell types among the neural tissue, including adult neural stem cells (aNSCs). Its remarkable up-regulation during neurodegeneration and its controversial signaling, ranging from survival to cell death, have attracted a special interest on this receptor as a potential pharmacological target. The association between p75NTR and Alzheimer’s Disease (AD) is of great interest in general, as p75NTR is highly expressed in degenerative populations in the development of AD pathology. p75NTR has been also extensively linked with AD by serving as a receptor for Amyloid-beta (Aβ), the major component of the plaques, found in the brain of AD patients. Furthermore, recent revolutionary studies are highlighting the importance of this receptor on the adult hippocampal neurogenesis, but contradictory results and lack of explicit methodology rather confuse the field, than defining the role of the receptor. Our study ranges from in vivo detection of adult neurogenesis in combined p75KO and AD mouse models to in vitro cell cultures. We reveal that the p75NTR is important to neurogenesis and the fate of aNSCs and we also explore the role of p75NTR in neurogenesis under the neuropathology of AD, as well. More specifically, this study focuses on the effects of p75NTR in adult neurogenesis of the dentate gyrus (DG) of rodent hippocampus, under physiological and neurodegenerative conditions, such as AD, as well as on examination of receptor's activity related to cell death or survival. By revealing and controlling the specific signaling pathways necessary to mediate the actions of p75NTR on stem cells, we could target the endogenous ability of neurogenesis. In the first part of our study, we evaluated the in vivo adult hippocampal neurogenesis in p75 knockout mice, compared to wildtype (2 months old and 6 months old mice). Our study was based on the evaluation of two different mouse models of p75 gene deletion. The first one, is the p75 ko Ngfrtm1Jae targeted mutation 1 -developed by Dr Rudolf Jaenisch and named p75NTR/ExonIII-, which lacks the full-length receptor. The second one is a conditional knock out which has a specific deletion of exon II in Nestin expressing cells based on the recombination of a p75NTRflox mouse with the Nestin/Cre mouse. Our results from the first mouse model are showing a significantly decreased number of proliferative aNSCs in p75 ko mice of 2 months old. These results are pointing out the necessity of p75NTR on adult neurogenesis. In a second step, we examined the effects of receptor’s deletion on the differentiation of aNSCs, using Dcx and NeuN markers and we gained results suggesting that immature neurons cannot proceed and differentiate into mature neurons. In parallel, we examined the mice with the specific p75 exonII deletion on Nestin+ cells. This mouse line provides significant evidence for the role of p75 in neurogenesis by defining the cell autonomous signaling pathways that are controlling stem cell fate. Finally, in order to investigate the role of p75NTR in a mouse model of Alzheimer’s Disease, we have crossed p75 ko exonIII with the 5xFAD mouse, an amyloid beta dependent mouse model of AD. In this mouse line, we also identify neurogenesis levels compared to wild-type as well. Additionally, we explore p75-dependent effects on human iPSCs-derived NPCs, in order to validate the results of the existing animal models but also to explore the effects of this neurotrophin receptor in human neurons, since these kind of studies are very rare till now, underlying the novelty of our work. Study of p75NTR involvement in human neurogenesis includes various research questions. Firstly, the expression and activity of p75NTR as well as its downstream mediators are identified. Moreover, we investigate p75NTR’s effects in human induced Pluripotent Stem Cells (hiPSCs)-derived NPCs, depicting receptor’s signaling and its dysregulation in NPCs derived from AD patients bearing the ApoE4 mutation. Furthermore, we study the role of the receptor in combination with the toxic effects of oligomerized Amyloid-beta, showing how p75NTR regulates hiPSCs-derived NPCs in the presence of Aβ amyloid, indicating its involvement in both AD progress and neurogenesis. These results provide useful information regarding the role of p75NTR in NPCs maintenance and its putative therapeutic role. In a pharmacological approach of our studies, we tested a chemical library of novel synthetic neurotrophin analogs in order to decipher the signaling properties of the receptor. These synthetic analogs are derived from dehydroepiandrosterone (DHEA), a previously shown activator of the receptor, and they were designed with preferable pharmacological properties that could selectively activate p75NTR and specific pathways that originate from this receptor. Despite the beneficial effects of neurotrophins on brain function, their therapeutic use is compromised due to their polypeptidic nature and blood–brain-barrier impermeability. To overcome these limitations, our previous studies have proven that small-sized, lipophilic, DHEA-derived synthetic analogs can exert neurotrophic effects, as they bind to specific neurotrophin receptors and thus they could be used as neurotrophin mimetics with favorable pharmacological properties. The present study also revealed the biological characterization of a newly synthesized analog, ENT-A044, and its role in inducing cell-specific functions of p75NTR. Treatment of cells with this compound showed a significant increase at cell death and pJNK expression, mediated by p75NTR in human iPSCs-derived NPCs as opposed to primary cell cultures derived from mice, where ENT-A044 led to survival. Thus, Neurotrophin Analog ENT-A044 Activates the p75 Neurotrophin Receptor, Regulating Neuronal Survival in a Cell Context-Dependent Manner. In conclusion, ENT-A044 is proposed as a lead molecule for the development of novel pharmacological agents, providing new therapeutic approaches and research tools, by controlling p75NTR actions. All the aforementioned studies offer valuable tools for selective control of p75NTR in AD, through the specific regulation of its endogenous neurogenic potential, as a novel repairing mechanism against neurodegeneration. In addition, adult neurogenesis consists a scientific field that has recently attracted special interest, although with many anticipating findings and strong arguments. The discovery of adult neurogenic potential in the brain opens new avenues and opportunities for treating neurological diseases, particularly through the exploitation of endogenous regenerative capacity. The detailed mapping of single cell properties and functions, based on the tempo-spatial expression of multifunctional regulatory receptors such as p75NTR, could provide an advantage for controlling neurogenesis and the related cognitive functions.
Language English
Subject Adult neurogenesis
Amyloid
Cell signaling
Degeneration
Hippocampus
Neural stem cells
Neuroregeneration
P75 receptor
Αμυλοειδές
Εκφύλιση
Ιππόκαμπος
Κυτταρική σηματοδότηση
Νευρικά βλαστικά κύτταρα
Νευροαναγεννητική ικανότητα
Νευροτροφίνες
Υποδοχέας νευροτροφινών P75
Issue date 2023-12-08
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/8/7/f/metadata-dlib-1700554901-27633-17393.tkl Bookmark and Share
Views 781

Digital Documents
No preview available

Download document
View document
Views : 2