Date

2022-8

Author

Ezgin, Sena

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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 (NT3), and neurotrophin-4/5 (NT4/5), and these factors mediate neuronal development, differentiation, cell survival, and synaptic plasticity through their high-affinity Tropomyosin receptor kinase (Trk) receptors. Modulation of neurotrophin signaling has been considered a potential therapeutic option against the neurodegenerative process of AD; however, there has been limited progress. A better understanding of critical residues in Trk receptors controlling neurotrophin signaling in neurons can potentially pave the road for manipulating the neurotrophin signaling in the AD context. To this end, a previous study from our group demonstrated that deletion of a conserved 3 amino acid domain (KFG domain) increases the TrkA receptor levels and enhances its signaling. NGF-mediated TrkA signaling play crucial roles in basal forebrain cholinergic neurons (BFCNs), which are among the most affected cell types in AD. Therefore, in this thesis, we focused on examining the effects of enhanced TrkA receptor signaling in BFCNs against the in vitro neurodegenerative process of AD, utilizing the KFG system established previously by our group. Towards this goal, we utilized WT and TrkA-KFG in which the KFG domain is deleted in TrkA mouse embryonic stem cells (mESCs), and differentiated the lines to BFCNs. We then characterized the differentiated neurons for their BFCN identity and established in vitro AD model utilizing amyloid-beta (Aβ(1-42)) toxicity. Our results demonstrated that KFG removal leads to increased TrkA levels and TrkA- KFG neurons are more resistant to Aβ(1-42)-mediated neuronal death compared to WT BFCNs. Our work further suggested that enhanced TrkA signaling can protect the synaptic density of BFCNs from Aβ(1-42)-mediated toxicity through the MAPK/Erk pathway. Our approach focusing on the enhanced NGF-TrkA signaling in the concept of in vitro AD differs from other studies in the literature because the aim here is to make the TrkA receptors more sensitive and active in specific neuron types instead of altering neurotrophin levels or influencing their receptors with small molecules.

Subject Keywords

Alzheimer’s Disease, Basal forebrain cholinergic neurons (BFCNs), Neurotrophin signaling, Nerve growth factor, Amyloid-beta (Aβ)

URI

https://hdl.handle.net/11511/98673

Collections

Graduate School of Natural and Applied Sciences, Thesis