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Alzboon, Walla' (2025) Impact of psychological stress and mammary tumour growth on structural and functional protein expression in cognitive brain areas. PhD thesis, University of Nottingham.

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Abstract

Aims: Cognitive impairments are commonly reported across breast cancer patients and frequently attributed to the toxic side effects of chemotherapy treatment. However, it is evident that 35% of breast cancer patients experience cognitive impairments prior to chemotherapy. This suggests that tumour growth itself and/or the diagnosis-related stress might contribute to the development of cancer-related cognitive impairments (CRCI). The main aim of this thesis is to investigate the effect of tumour growth and diagnosis-related stress on the development of pre-treatment cognitive impairments.

Methods: A mass spectrometry proteomics profiling of the hippocampus, prefrontal cortex, hypothalamus and cerebellum of the 3-month-old mice tissue was performed to investigate the effect of the tumour growth and restraint stress on the synaptic plasticity-related proteins. Moreover, immunohistochemistry (IHC) staining and western blot analysis were performed to validate the significantly changing proteins identified through proteomics analysis. To further study the effect of tumour growth on the cognitive brain regions (hippocampus and cerebellum), a 3-D in vitro co-culture model of the Py230 cells and organotypic brain slices was developed. Moreover, the secretomes of 3-D Py230 spheroids were investigated to enhance our understanding of what the spheroids were secreting in response to different pharmacological treatments such as TNF-α, IFN-γ, and cortisone treatment.

Results: Our results suggest that tumour growth itself and psychological stress affected the synaptic plasticity and myelin-related proteins, and consequently, cognitive functions such as learning, memory, and executive functions might be affected. Moreover, we successfully developed a unique model of the 3-D Py-230 spheroids that preserves the tumour growth microenvironment and the OTBSs, which maintain the brain tissue structure and function, such as synapse and microglial activity. Furthermore, the secretomes of Py230 spheroids were affected by pharmacological treatments such as TNF-α, IFN-γ, and cortisone treatment.

Conclusions: Tumour growth itself and restraint stress might affect cognitive-related domains such as memory, learning, decision-making, and other cognitive functions before the onset of breast cancer treatment. This cognitive impairment might be mainly explained by the neuroinflammation resulting from the tumour growth peripheral inflammation or the stress response.

Item Type:	Thesis (University of Nottingham only) (PhD)
Supervisors:	Sheridan, Graham Storr, Sarah Flint, Melanie
Keywords:	Proteomics, synaptosomes, cognitive brain regions, IHC staining, spheroids, organotypic brain slices, 3-D coculture model.
Subjects:	R Medicine > RC Internal medicine > RC 254 Neoplasms. Tumors. Oncology (including Cancer)
Faculties/Schools:	UK Campuses > Faculty of Medicine and Health Sciences > School of Life Sciences
Item ID:	80845
Depositing User:	Alzboon, Walla'
Date Deposited:	16 Apr 2025 04:40
Last Modified:	16 Apr 2025 04:40
URI:	https://eprints.nottingham.ac.uk/id/eprint/80845

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