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Title: Development of rodent in vivo models : neuroinflammation and neurodegeneration relevant to Alzheimer's disease
Author: Pugh, Perdita Lucy
ISNI:       0000 0004 2751 0705
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2007
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Alzheimer's disease (AD) is characterised by Ap plaque formation, neuroinflammation and neurodegeneration. Current therapies for AD do not modify disease progression therefore, putative anti-inflammatory and neuroprotective agents need to be assessed in rodent in vivo models that demonstrate robust and reproducible markers of neuroinflammation and neurodegeneration. This thesis interrogated the development of in vivo models comprising markers of neuroinflammation and neurodegeneration in rodent brain. The overview describes innate immunity focusing on lipopolysaccharide (LPS) as a standard immunostimulant followed by a review of AD and beta amyloid (Ap). Current rodent in vivo models of LPS or AP-induced neuroinflammation or neurodegeneration are also examined. Chapters 2 and 3 describe the novel application of Luminex suspension bead array systems for the detection of LPS-induced cytokine and other intracellular proteins in brain tissue. Intraperitoneal LPS modulated interleukin (IL)-lp, phosphorylated (p)-IicBa, p-p38 kinase and p-JNK protein and intracerebroventricular LPS increased IL-ip, IL-la and tumour necrosis factor (TNF) -a protein in rat brain. Cytokine protein in rat brain was abrogated by dexamethasone and the a2-adrenoceptor antagonist, fluparoxan. Subsequent chapters investigate more disease relevant models of Ap-induced neuroinflammation and neurodegeneration detected by immunohistochemistry, Taqman or Luminex techniques. Chapter 4 discussed the assessment, by western blotting, of Ap forms expelled from apparatus commonly used to inject solutions into rodent brain tissue and identifying the most consistent method of Ap delivery. Subsequent studies revealing inconsistent neurotoxicity but robust neuroinflammation following intra-hippocampal injection of Ap were described. Final chapters focus on neuroinflammation and neurodegeneration following peripheral insult (LPS or the noradrenergic neurotoxin, DSP-4) to amyloid precursor protein (APP) / presenilin 1 (PS1) transgenic mice. Peripheral administration of LPS or DSP-4 modulated markers of neuroinflammation and did not initiate neurodegeneration. The implications of the current data on the future development of in vivo models are discussed in the final chapter.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available