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Title: Biomarker profiling of ageing and neurodegenerative disease
Keywords: ageing, Alzheimer's disease, biomarker, metabolomics, steroid, mass spectrometry
Issue Date: 30-Jun-2009
Citation: (2009-06-30). Biomarker profiling of ageing and neurodegenerative disease. ScholarBank@NUS Repository.
Abstract: With the increasing life expectancy, the global aging population is expanding rapidly in the last few decades. In some cases, aging is accompanied by neurodegenerative diseases, such as Alzheimer's Disease (AD) and dementia. Early clinical intervention is crucial for the management and prognosis of AD patients as there is no cure for the disease thus far. However, the lack of specific and accurate biomarkers for its accurate diagnosis hinders the early clinical diagnosis and intervention of AD. In addition, the discovery and development of novel effective therapies for AD necessitate the use of reliable efficacy biomarker to facilitate and accelerate the clinical studies. Mass spectrometry (MS)-based metabonomics provides an important platform for the metabolic profiling of complex biological samples, which may lead to the discovery of biomarkers for the diagnosis of diseases. In this thesis, both non-targeted metabolic and targeted steroidal biomarker profiling of aging and AD were investigated using in vivo and in vitro models. The first objective was to characterize the global metabolic fluxes associated with aging and AD using GC/MS-based metabonomics and multivariate data analysis. Lister Hooded (LH) rat (2-month vs 2-year) and C57BL/6J mouse (1-month vs 5-month) models were analyzed using GC/MS to identify the small molecule metabolite markers of aging. In addition, both young and aged LH rats were treated with N1-lipoic acid, and their metabolic profiles were investigated and compared. To identify the metabolite markers of AD, the metabolic profiles of two transgenic AD mouse models, TASTPM and p25-induced mice, were examined and compared to those of wild type C57BL/6J mice. Moreover, an in vitro cortical neuron cell model was involved to investigate the changes in metabolic profiles associated with aging and glutamate-treatment, which may be implicated in the pathogenesis of AD. As endogenous steroid levels were found to be associated with aging and AD, the brain and plasma samples obtained from our animal models were further investigated for endogenous steroids using enzyme immunoassay. In addition, MS-based analytical techniques for the profiling of endogenous steroids in biological samples were investigated and compared. Our study demonstrated clear differences in metabolic profiles associated with aging and AD in both in vivo and in vitro models. A number of metabolites were found to be associated with the aging process and AD, with different markers being observed between different aging and AD animal models. In addition, the levels of endogenous steroids in brain and plasma of the animal models were found to be modified with aging and AD. While interesting and pertinent data were generated based on the MS-based assays for steroid analysis, none of the investigated methods was found to be suitable for the endogenous steroid profiling in complex biological samples. Our results suggested collectively that small molecule metabolites and steroids are promising biomarkers for the future study of aging and diagnosis of AD.
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