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Modulating The Unfolded Protein Response as a Therapeutic Target in Alzheimer’s Disease https://doi.org/10.17863/CAM.115792 Sidhom, Emad 0000000317338211 Underwood, Benjamin Dementia can be defined as a disturbance in memory and thinking which interferes with daily life. It is the leading cause of death in the UK, and dementia was estimated to cost the health service in England £24.2 billion in 2015. As such it is one of the major clinical problems of our time. The most common form of dementia is Alzheimer’s disease. Understanding the pathological underpinnings of Alzheimer’s disease (AD) could help devise effective treatments for it. One of the mechanisms that are implicated in Alzheimer’s disease is the unfolded protein response (UPR). Previous basic science work has suggested that the UPR becomes and remains activated during disease which stops or diminishes protein synthesis. This, in turn, means that proteins essential for synaptic and neuronal health are not produced and, this contributes to disease progression. Intervening in this process, therefore, provides an opportunity for therapeutic intervention. In this thesis, I present the results of a project designed to see if the activation of the UPR seen in cellular and animal models of disease also occurs in vivo in people with Alzheimer’s disease. Using positron emission tomography scanning following injection of L-[1-11C]-leucine as a radiolabelled ligand, we found that protein synthesis appears to be reduced in key regions of the brain associated with Alzheimer’s disease. We also found that the movement of leucine between plasma and cellular components of the brain appears to be significantly impaired in patients with Alzheimer’s disease. We have used the data from this study to inform the design of the next steps of potential experimental medicine studies to explore the impact of drugs on cerebral protein synthesis in people with Alzheimer’s disease. One drug proposed to inhibit the unfolded protein response is the antidepressant trazodone. Trazodone is a drug already in clinical use in patients with Alzheimer’s disease. We completed a retrospective cohort study using a pseudonymised electronic patient record to see whether patients with Alzheimer’s disease who are taking trazodone have different outcomes in patients who did not take trazodone. Whilst those taking trazodone did have a more extended period from diagnosis to death, the overall picture was that few people with dementia are prescribed trazodone; these are a select group of patients and almost x always at doses too low to impact the UPR. Our findings suggest that these records will not give a strong indication of any disease-modifying effect, and a clinical trial is therefore required to answer this question. Finally, I discuss the potential for the development of this work presented here with discussion of potential further experimental medicine approaches or moving to a clinical trial of trazodone University of Cambridge 2024-04-14 Thesis Doctoral Doctor of Medicine (MD) eng Gnodde Goldman Sachs Altos Labs https://www.repository.cam.ac.uk/handle/1810/379821 embargo 2031-02-17 https://www.repository.cam.ac.uk/bitstreams/abb5aeda-db1f-412b-9cba-a93aaa0d35d6/download dd67ad2f2774547d05552ddb12e464cb https://www.repository.cam.ac.uk/bitstreams/e9452ce5-7c00-4ff0-be4d-55ad823f1c04/download 87eda9de84448d1f82354d60eee3eb5f https://creativecommons.org/licenses/by-sa/4.0/ 11C-leucine Alzheimer's Disease cerebral protein synthesis database driven research Dementia ER stress response neurodegenerative disorders PET/MR protein aggregates unfolded protein response