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

Download

PeriBesarat_Msc_Thesis.pdf

Date

2023-1-20

Author

Beşarat, Peri

Metadata

Show full item record

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Item Usage Stats

265
views

83
downloads

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

URI

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

Collections

Graduate School of Natural and Applied Sciences, Thesis

Suggestions

OpenMETU
Core

COMPARATIVE ANALYSIS OF BRAIN CELL CULTURES AND TISSUES IN ALZHEIMER’S DISEASE BASED ON DIFFERENTIAL EXPRESSION AND GENE SET ENRICHMENT Burduroğlu, Hüseyin Cahit; Aydın Son, Yeşim; Department of Bioinformatics (2023-1-25) Alzheimer’s disease is currently the most common cause of dementia in the world. It is a neurodegenerative disease that is diagnosed neuropathologically by observing B-amyloid plaques and neurofibrillary tangles in the brain. Transcriptional differentiations, protein regulations, and the interactions in between have been investigated by recent studies to understand from which brain cell type the disease stems, such as microglia, astrocytes, and neurons. These studies are mostly performed on brain tiss...
A human carboxypeptidase E/NF-alpha 1 gene mutation in an Alzheimer's disease patient leads to dementia and depression in mice Cheng, Y.; Cawley, N. X.; Yanık, Tülin; Murthy, S. R. K.; Liu, C.; Kasikci, F.; Abebe, D.; Loh, Y. P. (2016-12-06) Patients with Alzheimer's disease (AD), a common dementia among the aging population, often also suffer from depression. This comorbidity is poorly understood. Although most forms of AD are not genetically inherited, we have identified a new human mutation in the carboxypeptidase E (CPE)/neurotrophic factor-alpha 1 (NF-alpha 1) gene from an AD patient that caused memory deficit and depressive-like behavior in transgenic mice. This mutation consists of three adenosine inserts, introducing nine amino acids, i...
Effects of enhanced TrkA signaling in mouse embryonic stem cell-derived basal forebrain cholinergic neurons against the in vitro neurodegenerative process of Alzheimer’s Disease Ezgin, Sena; Kiriş, Erkan; Department of Molecular Biology and Genetics (2022-8) Alzheimer's Disease (AD) is the most common neurodegenerative disease affecting more than 50 million people worldwide, and there is still no cure for AD despite extensive research efforts. The underlying cause of the disease is not well understood. Abnormal levels of neurotrophins and their receptors, and defects in neurotrophin signaling have long been correlated with AD. The neurotrophin family has four members, which are nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 ...
Investigating conversion from mild cognitive impairment to alzheimer's disease using latent space manipulation Ayvaz, Deniz Sezin; Baytaş, İnci M. (Orta Doğu Teknik Üniversitesi Enformatik Enstitüsü; 2022-10) Alzheimer’s disease, a progressive neurologic disorder, is the most common cause of dementia, affecting millions worldwide. Mild Cognitive Impairment (MCI) is considered an intermediate stage before Alzheimer's. Early prediction of the conversion from MCI to Alzheimer's is crucial to take necessary precautions for decelerating the disease progression and developing suitable treatments. This study proposes a deep learning framework to identify patients whose diagnoses might change from MCI to Alzheimer’s in ...
Gene-level pathogenicity scores for alzheimer’s disease using genomic variants from rna-seq data Bozkurt, Fatma Betül; İlgün, Atılay; Uzuner, Dilara; Çakır, Tunahan (Orta Doğu Teknik Üniversitesi Enformatik Enstitüsü; 2022-10) Alzheimer’s disease (AD) is a complex neurodegenerative disorder affecting millions of people worldwide. Next-generation sequencing technologies such as whole-exome/genome sequencing have been widely used for detecting the variants in the genome to understand the disease etiology and unravel underlying molecular mechanisms. Alternatively, RNA-Seq data can also be used to detect variants. Since AD is a complex disease, several variants are involved in the disease pathogenesis. By using scoring algorithms, it...

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.