Effects Of Enhanced TrkB Signaling In Mouse Embryonic Stem Cell-Derived Cortical Neurons Against Amyloid Beta 42-Mediated Cellular Events

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2023-1-20

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Beşarat, Peri

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Alzheimer’s Disease (AD) is the sixth most common cause of death globally. The disease causes memory loss and cognitive decline, eventually preventing the individual from performing simple actions in daily life. 2014-2018 Report of The Turkish Association of Alzheimer's indicates that there are at least 600,000 AD patients in Turkey and this number is expected to increase due to the rapidly aging population since AD is highly age-dependent. Despite extensive studies, there is currently no disease-modifying cure for AD. One of the therapeutic targets for AD is neurotrophin (NT) signaling as imbalances in the NTs and/or their receptor levels have been demonstrated in AD. Among the NT family of growth factors, brain-derived neurotrophic factor (BDNF) is extensively studied in AD as i) it is critical for the normal functioning of the adult nervous system, ii) BDNF and its receptor TrkB is downregulated in AD, and iii) in vitro and in vivo studies demonstrate the neuroprotective effects of BDNF against the AD process. BDNF activates its high-affinity receptor TrkB to regulate many vital processes in neurons, including synaptic plasticity, neurogenesis, and neuroprotection. Although BDNF’s potential benefits against AD are well appreciated, enhancing its signaling in the brain has been challenging for a number of reasons. Our group previously established that a highly conserved 3-aminoacid domain (KFG) of Trk receptors negatively impacts their signaling. The deletion of the KFG domain leads to an enhanced Trk activation and its downstream signaling. In this thesis, the aim was to utilize this TrkB-KFG model system to evaluate its effect against an in vitro AD model. To do so, WT and TrkB-KFG (KFG domain deletion) mouse embryonic stem cells (mESCs) were differentiated into cortical neurons, one of the most affected cell types in AD. Upon the generation and characterization of cortical neurons, an in vitro AD model was established using a well-characterized oligomeric Amyloid β(1-42) peptide (Aβ42). WT and TrkB-KFG cortical neurons were tested for viability, synaptic density changes, as well as for changes in BDNF-TrkB signaling pathways. We found that the KFG deletion leads to higher levels of TrkB receptors in TrkB-KFG cortical neurons. Importantly, TrkB-KFG cortical neurons exhibited a higher viability under Aβ42 insult compared to WT cortical neurons. Additionally, TrkB-KFG neurons exhibited resistance against synaptic density changes caused by oligomeric Aβ42 treatments as compared to WT cortical neurons. The novelty of this study lies in the TrkB-specific KFG modification which directly interferes with the TrkB receptor and does not have a known effect on anything other than TrkB, potentially creating a specific effect. To the best of our knowledge, this is the first study demonstrating the effects of enhanced TrkB signaling against AD, achieved by direct modulation of the receptor domains. This approach may be highly useful for future studies focusing on cell transplantation using modified cell sources.

Subject Keywords

Alzheimer’s Disease, Amyloid Beta, Cortical Neurons, TrkB Receptor, Brain-Derived Neurotrophic Factor

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https://hdl.handle.net/11511/102001

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Graduate School of Natural and Applied Sciences, Thesis

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Citation Formats

P. Beşarat, “Effects Of Enhanced TrkB Signaling In Mouse Embryonic Stem Cell-Derived Cortical Neurons Against Amyloid Beta 42-Mediated Cellular Events,” M.S. - Master of Science, Middle East Technical University, 2023.