Amyloid precursor protein processing and redox balance in the development of Alzheimer's disease

Alzheimer’s Disease (AD) is the leading cause of dementia and is characterised by progressive and irreversible neurodegeneration. The societal increase in average lifespan and trends in the prevalence of obesity are both associated with an increased risk of AD. Despite advancements in our understanding of the biochemical processes underlying AD, such as perturbed Amyloid- β Precursor Protein (AβPP) processing and disrupted redox homeostasis, finding new treatments that can prevent the neurodegenerative process has proved difficult. Recently, there has been growing interest in the ‘a disintegrin and metalloproteinase’ -10 (ADAM10) enzyme as both a biomarker for detecting AD and as a potential avenue for intervention. ADAM10 has been shown to have a favourable role in AβPP processing, therefore, strategies aimed at increasing ADAM10 enzymatic activity may hold therapeutic benefits. The thesis presented contains four empirical research chapters (chapters 3-6). In chapter 3, the research was focused on measuring peripheral markers associated non-amyloidogenic platelet AβPP processing, inflammation and oxidative stress in people who may be ‘at risk’ of AD. This research showed that lowered platelet ADAM10 and elevated markers of oxidative stress were associated with advancing age and obesity. However, there was no change in the AβPP isoform ratio. Lowered platelet ADAM10 has been previously shown to be predictive of AD and worsening cognitive function, this research suggests ADAM10 may a useful tool in determine people ‘at risk’ of AD. Research in chapter 4 focused on the characterisation of markers associated with AβPP processing and redox balance in induced pluripotent stem cell (iPSC) models carrying one of two PSEN1 mutations (L286V and R278I) compared to a healthy control line. The main findings demonstrated that AβPP processing was altered towards the pro-amyloidogenic pathway, with increased Aβ secretion, reduced ADAM10 protein levels and a lower AβPP ratio in both PSEN1 mutations. Further, markers of oxidative stress were typically elevated in PSEN1 mutations. These features are consistent characteristics identified in people with AD and therefore, this ‘in vitro’ model represents a functional system to study the early pathological features of AD. Work in chapter 5 investigated the functionality of the Serotonin-4 receptor (5HT4r) in the healthy control and L286V mutation carrying iPSC cortical models. This work extended to assess whether 5HT4r modulati