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Identifier

000440982

Title

Study on the effects of new synthetic and natural compounds in TrkB receptor on adult neurogenesis and in Alzheimer’s Disease

Alternative Title

Μελέτη της δράσης νέων συνθετικών και φυσικών ανάλογων νευροτροφινών στον υποδοχέα TrkB στην ενήλικη νευρογένεση και στην νόσο Αλτσχάιμερ

Author

Λυπίτκας, Δημήριος Θ.

Thesis advisor

Χαραλαμπόπουλος, Ιωάννης

Reviewer

Γραβάνης, Αχιλλέας
Κρετσόβαλη, Ανδρονίκη

Abstract

Neurodegenerative diseases, such as Alzheimer's disease, are characterized by progressive loss of structure or function of neurons in specific areas of the brain, like hippocampus, an area that has also been implicated in adult neurogenesis. Neurotrophins are growth factors with neuroprotective and neurogenic properties. Abnormal expression of neurotrophins and their receptors has been associated with the onset of neurodegenerative diseases. Recent studies have shown that small synthetic molecules that mimic the action of neurotrophins, known as microneurotrophins, can be used as potential treatment against neurodegenerative diseases. The aim of this master thesis is to screen such synthetic and natural molecules in vitro. More specifically, we aim to test their ability to activate the TrkB receptor (Tropomyosin related kinase B), which is the highly related endogenous neurotrophin receptor for Brain-Derived Neurotrophic Factor (BDNF). The neuroprotective properties of these molecules and the activation of pathways downstream of the receptor were tested in NIH3T3-TrkB cell line and primary astrocytes, as well as in neural stem cells (NSCs) isolated from mice. On this diploma thesis 42 synthetic compounds and natural extracts isolated from marine bacteria were screened. The compounds ENTA-011, ENTA-061, ENTA-0184 and the natural extract ENTA-M021 are these with the more positive abilities. ENTA-M021 and ENTA-0184, in the concentration of 1μΜ, increase the survival of NIH3T3- TrkB cells, phosphorylate the TrkB receptor and activate downstream kinases Akt and Erk1/2 in NIH3T3 TrkB cells and primary astrocytes. ENTA-011 and ENTA-061 induce survival of ΝΙΗ3Τ3-TrkB cells, phosphorylate TrkB receptor and downstream kinases Αkt, GSK3b and Erk1/2 in ΝΙΗ3Τ3-TrkB cells, primary astrocytes and neural stem cells (NSCs). Additionally, the actions of ENTA-011 and ENTA-061 are blocked by the selective TrkB inhibitor ANA-12. Finally, ENTA-011 and ENTA-061 promote proliferation of ΝSCs in the presence of toxic Amyloid β oligomers. ENTA-011 and ENTA-061 exert all of these actions in a concentration of 1μM and they have rapid action on TrkB phosphorylation upon 10 min of treatment. During this master thesis, we also examined the role of the transmembrane domain of TrkB receptor, showing that it has an important and necessary role in the signaling of BDNF and TrkB receptor activating compounds. Our results clearly indicate the neurotrophic role of ENTA-011 and ENTA-061. In next studies, ENTA-011 and ENTA-061 will be administered on a mouse model of Alzheimer's disease, the 5xFAD mice, in order to examine their in vivo neuroprotective and neurogenic effects.

Language

English

Subject

Neurotrophins

TRKB υποδοχέας

Νευροτροφίνες

Issue date

2021-07-30

Collection

School/Department--School of Sciences and Engineering--Department of Biology--Post-graduate theses

Type of Work--Post-graduate theses

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