Risk Factors For Alzheimer's Disease
Alzheimer’s disease is a neurodegenerative disorder characterized clinically by progressive cognitive impairment [1]. Age is the most important factor that predisposes persons to the non-familial form of the disease, which in 2010 affected over 35 million elderly adults worldwide [2]. How aging interacts with other risk factors for Alzheimer’s disease [3] is still unknown. It appears, however, that certain age-related pathologies that are closely associated with systemic dysfunctions in lipid metabolism –including obesity and diabetes –might be involved [1]. The polyunsaturated lipid, docosahexaenoic acid (C22:6n-3), is an essential component of neuronal membranes [4,5] and a precursor for potent neuroprotective mediators [6–8]. Mammals obtain
docosahexaenoic acid directly from dietary sources, especially fish, but can also produce it in liver from n-3 fatty acid precursors present in plants [9–11]. When the diet does not PLoS ONE | www.plosone.org provide an adequate supply of these foods, as is often the case in contemporary populations [12], the liver’s capacity to generate docosahexaenoic acid may become critical to keep normal the brain levels of this fatty acid [9,11,13,14]. Figure 1 shows an overview of liver docosahexaenoic acid biosynthesis. Elongase and desaturase enzymes localized in the endoplasmic reticulum of the hepatocyte progressively add carbon units and double bonds to shorter-chain n-3 fatty acids, producing the very-long-chain tetracosahexaenoic acid (C24:6n-3). This is transported into peroxisomes and then converted to docosahexaenoic acid by the sequential action of acyl-coenzyme A oxidases, D-bifunctional protein and peroxisomal thiolases [15–18]. Liverderived docosahexaenoic acid reaches the brain through the circulation, probably bound to proteins that are also synthesized by hepatocytes [9]. Evidence indicates that docosahexaenoic acid serves important neurotrophic functions during early mammalian development 1 September 2010 | Volum
docosahexaenoic acid directly from dietary sources, especially fish, but can also produce it in liver from n-3 fatty acid precursors present in plants [9–11]. When the diet does not PLoS ONE | www.plosone.org provide an adequate supply of these foods, as is often the case in contemporary populations [12], the liver’s capacity to generate docosahexaenoic acid may become critical to keep normal the brain levels of this fatty acid [9,11,13,14]. Figure 1 shows an overview of liver docosahexaenoic acid biosynthesis. Elongase and desaturase enzymes localized in the endoplasmic reticulum of the hepatocyte progressively add carbon units and double bonds to shorter-chain n-3 fatty acids, producing the very-long-chain tetracosahexaenoic acid (C24:6n-3). This is transported into peroxisomes and then converted to docosahexaenoic acid by the sequential action of acyl-coenzyme A oxidases, D-bifunctional protein and peroxisomal thiolases [15–18]. Liverderived docosahexaenoic acid reaches the brain through the circulation, probably bound to proteins that are also synthesized by hepatocytes [9]. Evidence indicates that docosahexaenoic acid serves important neurotrophic functions during early mammalian development 1 September 2010 | Volum