DNA damage and nutrient status as risk factors for mild cognitive impairment and Alzheimer’s disease

The incidence of neurodegenerative diseases such as Alzheimer’s disease (AD), which has an Australian prevalence of over 320,000, is expected to increase 3 fold in the next 30 years as a result of Australia’s ageing population. Currently, 24.3 million people worldwide are diagnosed as having AD, with 4.6 million new cases being clinically diagnosed each year. Alzheimer’s disease (AD) is associated with the abnormal increased accumulation of extracellular beta amyloid peptide 42 (Aβ42), which creates neurotoxic plaques in the brains of AD patients who have also been found to have increased rates of DNA damage events in different tissues, such as brain, buccal cells and peripheral blood lymphocytes. Previous studies have shown that mild cognitive impairment (MCI) may reflect the early stages of more pronounced neurodegenerative disorders such as AD. To date, conclusive diagnostic tests and the impact of dietary status for neurodegenerative disease risk have not been clearly defined. Therefore, it is important to identify potential DNA damage biomarkers and plasma micronutrient profiles associated with MCI and AD that may aid in understanding the biology of the disease and inform the design of potential dietary preventative measures. The content of this thesis comprises 2 distinct parts. For the in vitro study, the aim was: (i) To determine whether extracellular Aβ40 or Aβ42 induces chromosomal DNA damage and cell death in human peripheral lymphocytes (ii) To investigate whether there is an interactive effect between extracellular Aβ and folic acid status For the in vivo cross-sectional study, the aim was: (i) To investigate whether human peripheral blood lymphocytes of newly diagnosed MCI and AD cases have a different spontaneous chromosomal DNA damage biomarker profile relative to healthy age- and gender-matched controls in an Australian population (ii) To identify an array of important micronutrients, organ function and stress markers in plasma associated with MCI or AD diagnosis prior to medication and to compare these profiles to those observed in healthy age- and gender- matched controls (iii) To determine lipid status, including plasma cholesterol and triglycerides, and red blood cell fatty acid profiles of newly diagnosed MCI or AD individuals relative to healthy age- and gender- matched controls The cytokinesis-block micronucleus cytome (CBMN-Cyt) assay was the main assay used in these experiments as previous studies conducted at CSIRO (Nutrigenomics and Genome Health Laboratory) have shown that lymphocytes are an ideal tool for measuring the effect of genome stability (e.g. micronuclei, nucleoplasmic bridges, and nuclear buds) in cells exposed to endogenous or exogenous genotoxins or under conditions of micronutrient deficiency. Findings from the in vitro study showed that (i) extracellular Aβ40 is not genotoxic or cytotoxic, (ii) extracellular Aβ42 reduces nuclear division capacity and induces significantly elevated rates of necrosis in human peripheral lymphocytes, but does not appear to have a strong effect on chromosomal DNA damage markers in the CBMNCyt assay and (iii) no interactive effect was found between folic acid and extracellular Aβ42. Results from the in vivo study showed that (i) the genome instability biomarker, nuclear buds, is significantly elevated in South Australians with MCI and, together with micronuclei and nucleoplasmic bridges, is associated with poor global cognitive function scores as measured using the Mini-Mental State Examination, (ii) micronutrients, organ function and stress biomarker profiles in plasma are significantly altered in newly diagnosed MCI and AD individuals compared to healthy controls, and (iii) lipid profiles are also significantly altered in newly diagnosed MCI and AD cases compared to healthy controls. These findings shed some light on the etiopathogenesis of MCI and AD, which may be relevant in identifying those at increased risk of these neurodegenerative diseases and in determining the design and assessing the efficacy of future intervention studies.

Author dc:creator

• Lee, Sau Lai

Advisors dc:contributor.advisor

• Fenech, Michael Felix
• Thomas, Philip

• DNA damage
• nutrient
• mild cognitive impairment
• Alzheimer's disease

Handle dc:identifier.uri

http://hdl.handle.net/2440/101474

OAI identifier oai:identifier

oai:digital.library.adelaide.edu.au:2440/101474