| Abstract |
Recent studies indicate that myelin destruction is a critical early event in Alzheimer's Disease (AD) and acts as an exacerbating factor in its progression. However, it remains unclear whether myelin loss is due to oligodendrocytes becoming more vulnerable, reduced repair capacity, or exposure to other toxic environmental stimuli. This dissertation spatially and temporally examined myelin destruction and the population of precursor oligodendrocytes (OPCs) in the brain of 5xFAD transgenic mice (a mouse model of AD). Οur results show that DG is the most severely affected hippocampal area in terms of amyloid levels, OPC and myelin reduction and suggest a link between decreased number of OPCs and a high load of amyloid-β.
Analysis of neurotrophin receptor expression in OPCs was conducted to identify new targets that could enhance the myelination of nerve fibers. Neurotrophins constitute a family of secreted proteins, with Nerve Growth Factor (NGF) and Brain Derived Neurotrophin Factor (BDNF) being the most prominent members of this family. They regulate the development and survival of neurons, also influencing neural and synaptic function in the adult brain through specific receptors, such as TrkA for NGF and TrkB for BDNF. Numerous studies have demonstrated that the processing and expression levels of neurotrophins are dysregulated in Alzheimer's Disease (AD), contributing significantly to the pathology of the condition. Brain-derived neurotrophic factor (BDNF) is known to selectively act through the TrkB receptor, promoting axon remyelination, OPC proliferation, and differentiation. This study demonstrated that BDNF prevents OPC death and promotes their proliferation and differentiation after exposure to the toxic form of Amyloid-β 1-42 in vitro.
However, natural neurotrophins have short half-lives, difficulty crossing the blood-brain barrier, and low pharmacokinetic profiles. In this context, our laboratory identified in previous studies the molecules BNN27 and BNN20, two small derivatives of DHEA that interact with the TrkA, TrkB, and p75 receptors, exhibiting similarities to certain actions of NGF or BDNF, such as the protection of specific neuronal populations from degeneration. The present study highlighted the ability of BNN27 to promote the proliferation of OPCs as well as the differentiation of neural stem cells (NSCs) into OPCs under physiological and neurodegenerative conditions in vitro. Such molecules demonstrate significant potential as therapeutic agents against neurodegenerative diseases, as they can selectively mimic specific beneficial neurotrophic actions, thereby avoiding undesirable side effects.
In our research effort, we focused on developing new synthetic analogs of BDNF, initially evaluating the properties of 40 newly synthesized small molecules. Some of these new compounds exhibited neuroprotective effects under stress conditions through the selective activation of the TrkB receptor. Further investigation of the most effective molecules revealed the capacity of one of them, TC509, to promote the differentiation of neural stem cells into oligodendrocyte precursor cells (OPCs) both in the presence and absence of amyloid-β. Micro-neurotrophin TC509 also appeared to induce the maturation of OPCs into mature oligodendrocytes under both physiological and neurodegenerative conditions. Additionally, administration of TC509 to OPCs in the presence of amyloid-β succeeded in protecting them from cell death. The neuroprotective action of this molecule was corroborated by its ability to rescue human neural stem cells from death under neurodegenerative conditions. Consequently, this study revealed a new compound, micro-neurotrophin TC509, which exhibited anti-apoptotic effects and selectively promoted the differentiation and maturation of OPCs into mature oligodendrocytes through the TrkB receptor.
In conclusion, this dissertation characterizes spatial and temporal myelin destruction and OPC loss in the brain under Alzheimer's conditions in vivo. It highlights the protective role of BDNF under neurodegenerative conditions in vitro and proposes a newly synthesized small molecule that promotes the survival and remyelination of nerve cells as a novel complementary therapeutic approach for the disease and a potential therapeutic strategy for various demyelinating disorders.
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