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Identifier

000456124

Title

Evaluation of microneurotrophins activity on neurotrophins receptors and their role in signalling, in in vitro and in vivo neurodegenerative conditions such as Alzheimer's disease

Alternative Title

Αξιολόγηση της δράσης των μικρονευροτροφινών στους υποδοχείς των νευροτροφινών και ο ρόλος τους στη σηματοδότηση , σε in vitro και in vivo μοντέλα νευροεκφυλιστικών ασθενειών όπως η νόσος Αλτσχάιμερ

Author

Ρογδάκης, Αθανάσιος

Thesis advisor

Γραβάνης, Αχιλλέας

Reviewer

Χαραλαμπόπουλος, Ιωάννης

Abstract

Alzheimer’s Disease is a devastating neurodegenerative disorder, which currently affects more than 50 million people worldwide. Clinically, the disease is characterized by cognitive impairment, including severe memory loss, that results in patients having difficulties in performing simple everyday tasks. Pathologically, the hallmarks of the disease include the deposition of amyloid-β plaques extracellularly and the presence of hyperphosphorylated neurofibrillary tau tangles intracellularly. Neurotrophins are a family of secreted proteins, with Nerve Growth Factor (NGF) and Brain-Derived Neurotrophin Factor (BDNF) as the most prominent family members. These control neuronal development and survival and have also been shown to modulate neuronal and synaptic function in adult brain, acting through specific high-affinity receptors, namely TrkA for NGF and TrkB for BDNF. Moreover, all neurotrophins activate the p75 pan-neurotrophin receptor although with variable affinity. Many studies have shown that neurotrophins’ processing and expression levels are deregulated in AD, and this has been postulated to significantly contribute to the disease pathophysiology. Our lab has previously identified BNN27 and BNN20, two small molecules DHEA derivatives that act through TrkA, TrkB and p75 receptor in a way that resembles some of the NGF or BDNF actions, such as protecting specific neuronal populations against apoptosis. Such molecules present great potential as therapeutic agents against neurodegenerative diseases, as they can selectively mimic only specific, beneficial neurotrophic actions while avoiding undesired side effects. For the present PhD thesis, we screened and identified a series of neurotrophin analogues, which can selectively bind and activate neurotrophin receptors. Specifically, we used cell lines to identify novel small molecule DHEA derivatives that can selectively activate TrkA and can protect against cell death. These molecules, along with few more selective for TrkB were then screened using primary neuronal cells challenged with the toxic Aβ oligomers for their ability to protect cells against Aβ-mediated cell death and synapse degeneration. Lastly, we selected one potent TrkB agonist and tested it in vivo in the 5xFAD animal model of AD. 4-month-old animals were treated for 2 months with the drug and the efficacy of the drug to reverse the behavioural deficits was evaluated. More specifically, we showed that ENT-A061-treated 5xFAD animals showed improved ability to discriminate between environments based on context compared to placebo-treated 5xFAD littermates in the contextual fear discrimination paradigm, and similar to WT animals, a process that has been correlated with increased neurogenesis. In conclusion, ENT-A061 showed promise in improving certain aspects of AD pathology by enhancing adult hippocampal neurogenesis.

Language

English

Subject

Drug design and characterization

Drug development

Pharmacology

Ανάπτυξη και χαρακτηρισμός φαρμάκων

Αξιολόγηση φαρμάκων

Νευροτροφίνες

Φαρμακολογία

Issue date

2023-07-28