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Identifier

000463779

Title

In vivo study of synthetic neurotrophin analogs in the 5xFAD animal model of Alzheimers disease

Alternative Title

In vivo μελέτη συνθετικών αναλόγων νευροτροφινών στο ζωϊκό μοντέλο 5xFAD της Νόσου Αλτζχάιμερ

Author

Βελισσαρίου, Μαρουσώ

Thesis advisor

Χαραλαμπόπουλος, Ιωάννης

Reviewer

Σιδηροπούλου, Κυριακή
Φρουδαράκης, Εμμανουήλ

Abstract

Neurotrophins are a family of growth factors including NGF, BDNF, NT3, NT4, and promote the survival, development, and even apoptosis of neurons. These growth factors exert their functions through specific transmembrane receptors to which they bind. The two main categories of neurotrophin receptors are p75NTR and TRK receptors, which are further subdivided into TRKA, TRKB, and TRKC. Each TRK receptor has specific binding sites for different neurotrophin families; namely, NGF binds to TRKA, BDNF and NT4 to TRKB, and NTR3 to TRKC. Following the binding of neurotrophins to TRK receptors, these receptors dimerize, subsequently activating signaling pathways that lead to neuronal survival or differentiation. In the neurodegenerative disease Alzheimer's disease, neuronal apoptosis and loss of synaptic connections are observed in the cortex. Previous studies have shown that neurotrophin production is reduced in a degenerated brain, leaving neurons unprotected from apoptosis. This makes neurotrophins and cellular apoptosis an important therapeutic target for such diseases. However, neurotrophins are unable to cross the blood-brain barrier and have poor pharmacokinetics. For these reasons, this study will investigate a novel synthetic agonist, specific and selective for the TRKB neurotrophin receptor, ENT-A061. This agonist has been shown to have neuroprotective and neuroregenerative properties in primary neuronal cell cultures. The structure of ENT-A061 is based on that of BNN27, a synthetic microneurotrophin, which is a neurosteroid derivative, can cross the blood-brain barrier, and is specific for the receptor to which it binds. In this study, the properties of the agonist ENT-A061 will be examined through its effects on male hemizygous 5xFAD genotype mice and wild-type male mice. 5xFAD mice express human genes (e.g., APP) with a set of five mutations that have been associated with Alzheimer's disease and exhibit its phenotypes, such as neuronal loss and amyloid plaque accumulation. Mice from both the 5xFAD and wild-type genotype categories will be administered the agonist ENT-A061 as well as placebo, thereby creating four different groups. All animals will undergo behavioral memory tests. Following these experiments, the brains of the animals will be isolated for histological and biochemical analyses.

Language

English

Subject

Plaques

Αμυλοειδές

Νευροτροφίνες

Issue date

2024-04-17

Collection

School/Department--School of Medicine--Department of Medicine--Post-graduate theses

Type of Work--Post-graduate theses

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