Year

2015

Degree Name

Doctor of Philosophy

Department

School of Medicine

Abstract

The world’s population is rapidly ageing, and with that has come a corresponding increase in the number of people suffering age-related diseases. Dementia is a group of age-related neurocognitive disorders, with the most common of these being Alzheimer’s disease (AD). The number one risk factor for developing AD is advanced age, with the incidence rising from 1 in 10,000 at age 60 to 1 in 3 by age 85. AD is characterised by the deposition of extracellular amyloid-β aggregates (Aβ) and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau. Both Aβ and NFTs spread throughout the brain by separate but predictable pathways during the progression of the disease. Many studies have shown an involvement of membrane lipids, including phospholipids, in the pathogenesis of AD. Less is known about the changes occurring in membrane lipids such as phospholipids within the brain over the normal adult lifespan. Lipids are major components of the brain comprising 40-55% of the dry matter present, with phospholipids making up half of total brain lipid. The human brain undergoes a number of structural changes during the course of ageing that could theoretically lead to alterations in brain phospholipids. Changes to phospholipids with age within the human brain could be driven by two current theories of ageing: i) the mitochondrial free radical oxidative stress theory of ageing, which proposes that ageing is driven by damage to macromolecules such as lipids by reactive oxygen species produced by the mitochondria; or ii) the “inflammageing” theory, which suggests that ageing is driven by chronic, low-grade inflammation over the lifetime of an organism. Several studies conducted over twenty years ago attempted to characterise any changes occurring to brain phospholipids with age, but newer methods utilising mass spectrometry to identify and quantify lipids have become available since then. Understanding the changes occurring to phospholipids during normal ageing may lead to a better interpretation of the changes occurring during AD while also clarifying what fundamental mechanism underpins ageing within the human brain.

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