Inflammation in the brain has been strongly implicated in the development and progression of Parkinson’s disease (PD). Neuroinflammation in PD is thought to occur in response to aberrant α-synuclein aggregates, and may be mediated by Toll-like receptors (TLRs). TLRs are pattern recognition receptors with the ability to detect damage-associated molecular patterns. The activation of TLRs, potentially occurring through the detection of aggregated α-synuclein, triggers the release of pro-inflammatory cytokines. This may result in chronic inflammation, which produces an environment toxic to neurons and thus causes neurodegeneration such as that seen in the substantia nigra of the PD brain. I hypothesise that the blockade of TLRs will result in the slowing of pathological progression in an animal model, and the blockade of an α-synuclein inflammatory response in human PBMCs.

Chapter 1 describes the clinical and pathological characteristics of PD and some of the suggested mechanisms behind the progression of pathology, focusing on neuroinflammation. Additionally, it introduces TLRs and summarises the current literature surrounding their connection to PD, in particular that of TLRs 2 and 4.

Chapter 2 describes the reproduction of the Kuan et al., (2019) α-synuclein animal model, including behavioural and neuropathological features. To test the effect of TLR blockade on the development of pathology the drug candesartan was used. This is a licensed drug used in the treatment of hypertension through its action as an AT₁ receptor blocker, but has also been identified as decreasing the expression of TLRs 2 and 4. This work demonstrated a protective effect of TLR blockade on the development of cholinergic neurodegeneration and olfactory deficits, both features of early human PD.

Chapter 3 investigates the mechanism behind the protective effects of candesartan seen in chapter 2. Candesartan showed only small trends towards decreasing the expression and protein levels of TLRs 2 and 4. Neuroinflammation was not identified within the brain, and thus candesartan did not appear to have any effects on this inflammation. Peripheral inflammation was identified at a 2-month timepoint, and candesartan decreased this inflammation, providing a potential protective mechanism.

Chapter 4 describes the optimisation of an in vitro assay to investigate the inflammatory response of human peripheral immune cells to different forms of α-synuclein. This work showed that human peripheral immune cells show a pro-inflammatory response to both monomeric and oligomeric α-synuclein, and that this is blocked using candesartan. This response was shown to be TLR4- but not TLR2-dependent.

Chapter 5 summarises the main conclusions of my thesis. Candesartan is having a protective effect on the development of neurodegeneration within the α-synuclein animal model, however the mechanisms behind this are unclear. This protective effect could arise through the suppression of peripheral inflammation, through the inhibition of autophagy through decreasing the expression of TLRs on neurons, or through the blockade of AT1 receptors. Further evidence supporting an anti-inflammatory mechanism arises from the decrease in α-synuclein-mediated inflammation in in vitro human peripheral immune cells on candesartan treatment. This thesis finishes with suggestions for further work to provide more insight into the mechanisms behind the protective action of candesartan, and to provide further rationale for the use of candesartan in a clinical trial.