Oxidized cholesterol as the driving force behind the development of Alzheimer's disease

Abstract

Alzheimer's disease (AD), the most common neurodegenerative disorder associated with dementia, is typified by the pathological accumulation of amyloid Aβ peptides and neurofibrillary tangles (NFT) within the brain. Considerable evidence indicates that many events contribute to AD progression, including oxidative stress, inflammation, and altered cholesterol metabolism. The brain's high lipid content makes it particularly vulnerable to oxidative species, with the consequent enhancement of lipid peroxidation and cholesterol oxidation, and the subsequent formation of end products, mainly 4-hydroxynonenal and oxysterols, respectively from the two processes. The chronic inflammatory events observed in the AD brain include activation of microglia and astrocytes, together with enhancement of inflammatory molecule and free radical release. Along with glial cells, neurons themselves have been found to contribute to neuroinflammation in the AD brain, by serving as sources of inflammatory mediators. Oxidative stress is intimately associated with neuroinflammation, and a vicious circle has been found to connect oxidative stress and inflammation in AD. Alongside oxidative stress and inflammation, altered cholesterol metabolism and hypercholesterolemia also significantly contribute to neuronal damage and to progression of AD. Increasing evidence is now consolidating the hypothesis that oxidized cholesterol is the driving force behind the development of AD, and that oxysterols are the link connecting the disease to altered cholesterol metabolism in the brain and hypercholesterolemia; this is because of the ability of oxysterols, unlike cholesterol, to cross the blood brain barrier (BBB). The key role of oxysterols in AD pathogenesis has been strongly supported by research pointing to their involvement in modulating neuroinflammation, Aβ accumulation, and cell death. This review highlights the key role played by cholesterol and oxysterols in the brain in AD pathogenesis.

Keywords: Alzheimer’s disease; inflammation; oxidative stress; oxidized cholesterol; oxysterols.

Figure 1

A vicious circle connects oxidative stress, inflammation, and neurodegeneration in Alzheimer’s disease (AD). Oxidative stress damage and inflammatory response are closely associated with AD, causing neurodegeneration. Oxidative stress induces activation of microglia and astrocytes with a consequent increase of pro-inflammatory mediator production and, in turn, glial activation leads to toxic radical release, exacerbating neuronal damage. Consequently, the resultant cellular damage amplifies the inflammatory response, with glial activation and leukocyte recruitment, leading to further inflammation in the AD brain. The release of inflammatory cytokines leads to amyloid plaque and neurofibrillary tangle (NFT) formation, that triggers inflammatory molecule release and causes neuronal damage, with consequent neurodegeneration.

Figure 2

Enzymatically and non-enzymatically produced oxysterols in AD brain and their fluxes across the blood brain barrier (BBB). In neuronal cells, cholesterol is converted into 24-hydroxycholesterol (24-OH) by the enzyme CYP46A1; 24-OH, unlike cholesterol, diffuses across the BBB into the systemic circulation. To a lesser extent, cholesterol is also converted into 27-hydroxycholesterol (27-OH) by the enzyme CYP27A1, and then into 7α-hydroxy-3-oxo-4-cholestenoic acid (7-OH-4-C) by the enzyme CYP7B; crossing the BBB, 7-OH-4-C reaches the liver where it is eliminated. However, most 27-OH flows from the circulation into the brain, since it can cross the BBB. In addition, other oxysterols, such as 7β-hydroxycholesterol (7β-OH), 7-ketocholesterol (7-K), 7α-hydroxycholesterol (7α-OH), 4β-hydroxycholestrerol (4β-OH), 5α, 6α- and 5β, 6β-epoxicholesterol (α- and β-EPOX), and 25-hydroxycholesterol (25-OH), have been found in AD brain deriving from brain cholesterol autoxidation. Potentially these oxysterols, as well as other cholesterol metabolites, can cross the BBB.