Linking amyloid, inflammation and lipids to Alzheimer’s Disease using state-of-the-art imaging techniques

Lobanova, Evgeniia 2019. Linking amyloid, inflammation and lipids to Alzheimer’s Disease using state-of-the-art imaging techniques. PhD Thesis, Cardiff University. Item availability restricted.

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Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia in the elderly. The extracellular accumulation of amyloid-β (Aβ) in senile plaques is a principal event in the pathogenesis and there is growing evidence that the dysregulation of lipid pathways and neuroinflammation are implicated in the disease, however the link between these three is still under study. My multidisciplinary PhD study utilizes label-free Raman micro-spectroscopy combined with quantitative image analysis and high-resolution fluorescent microscopy to investigate the spatio-chemical composition and correlation of Aβ plaques with both neuroinflammatory biomarkers and lipids in post-mortem AD human brains. The results have proved the capability of Raman micro-spectroscopy to identify novel chemical imaging biomarkers of oxidative damage and neuroinflammation, colocalized to Aβ-affected regions of AD human brains, thereby delivering a useful imaging tool for detecting molecular signs of AD tissue neuropathology without the use of dyes or labels. Along with a pathogenic Aβ protein, two types of lipid aggregates co-depositing with the Aβ plaques of AD brains and in spectral characteristics resembling oxidized forms of free polyunsaturated fatty acids (FAs) and saturated cholesteryl esters (CEs) were found in this study. Correlation of the label-free Raman images of unmixed lipids with confocal fluorescence microscopy of the immunolabelled pro-inflammatory markers of AD brains revealed the CE lipidomic halo around the Aβ plaque co-localizing with significant ASC speck and pore-forming gasdermin D accumulations in the membrane of the NLRP3 inflammasome-activated microglia. Also, Raman micro-spectroscopy combined with fluorescence microscopy of Aβ pathology lesions in diseased tissues allowed to find colocalization of a pore-forming protein component 9 of a membrane attack complex (MAC) with the ASC specks and calcium crystals in the Aβ plaque cores, possibly reflecting the MAC as a driver of neuroinflammation and oxidative damage in AD. Thus, my thesis proposes Raman micro-spectroscopy profiles of the oxidized lipids and calcium crystals as novel biomarkers for label-free chemically specific and non-destructive imaging of Aβ-associated neuropathology and neuroinflammation in AD human brains.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Medicine
Date of First Compliant Deposit:	18 May 2020
Last Modified:	13 Mar 2021 02:24
URI:	https://orca.cardiff.ac.uk/id/eprint/131621

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