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Identifier 000443448
Title In vitro study of the activity of new synthetic and natural neurotrophin analogues on TrkA receptor and in Alzheimer’s disease
Alternative Title In vitro μελέτη της δραστικότητας νέων συνθετικών και φυσικών αναλόγων νευροτροφινών στον υποδοχέα TrkA και στη νόσο Αλτσχάιμερ
Author Παπαδημητρίου, Ελένη Κ.
Thesis advisor Χαραλαμπόπουλος, Ιωάννης
Abstract Alzheimer is a neurodegenerative disease characterized by progressive loss of structure and function of neurons in central nervous system, leading to cognitive decline, dementia and eventually death. Neurotrophins and their receptors have been highly correlated with Alzheimer’s disease as either their expression decreases during the progress of the disease or their pathological isoforms appear. Neurotrophins are growth factors with neurogenic and neuroprotective properties. They act by binding either to their high – affinity receptors Trks or to p75NTR receptor. Despite their multiple beneficial effects, their therapeutic potential is limited due to their polypeptidic nature, as well as, their inability to cross blood – brain barrier (BBB). Recent studies of our laboratory have demonstrated the ability of endogenous neurosteroid dehydroepiandrosterone (DHEA) to inhibit neuronal apoptosis by selectively binding to neurotrophin receptors, TrkA and p75NTR. However, DHEA is metabolized in vivo to androgenic and estrogenic steroids, thus may increase the risk of developing hormone - depented cancer. To overcome these problems, our chemists collaborators synthesized DHEA analogues, which sustain the neuroprotective actions of the parental molecule while are deprived of the endocrine effects. The aim of this master thesis is firstly to screen such synthetic and natural molecules in vitro and subsequently to estimate their biological effects. More specifically, we aim to test their ability to activate the TrkA receptor (Tropomyosin related kinase A), which is the highly – affinity endogenous neurotrophin receptor for Nerve Growth Factor (NGF). The neuroprotective properties of these molecules and the activation of downstream pathways of the receptor were tested in PC12 cell line and primary hippocampal neurons isolated from mice. On this diploma thesis 46 synthetic compounds and natural extracts isolated from marine bacteria were screened. Compounds ENTA-005, ENTA-010, ENTA-013, ENTA-013E, ENTA-013Z and ENTA-040, in the concentration of 500 nM and 30 minutes after treatment, were able to induce TrkA phosphorylation and provoke downstream signaling, as well as, protect cells from apoptosis after serum deprivation. Furthermore, the ability of the compounds to act selectively though TrkA and TrkB receptor, was tested and confirmed. The efficiency of the compounds to reverse the apoptotic effects indiced by the toxic Aβ oligomers was tested. Finally, we examined the role of the transmembrane domain of Trk receptors, showing that it has an important and necessary role in neurotrophins’ and compounds’ signaling.
Language English
Subject Neurodegeneration
TRKA υποδοχέας
Υποδοχείς νευροτροφινών
Issue date 2021-11-26
Collection   School/Department--School of Sciences and Engineering--Department of Biology--Post-graduate theses
  Type of Work--Post-graduate theses
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