The role of Toll-like receptors in Parkinson's disease
type: CreativeWork
description: 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…
abstract: 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…
author: Kennedy, Catherine
language: eng
keywords: Parkinson's disease, Toll-like receptors
license: https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/c4bbd9a4-5668-4874-8c32-79af78894d3b/download
license: https://www.rioxx.net/licenses/all-rights-reserved/
date published: 2023-05
date modified: 2026-07-22T22:24:20Z
provider: Cambridge University
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Cambridge

PropertyValue
property ID: DOI
value: 10.17863/CAM.106123