Theorizing on Oxidized Cholesterol as a Driving Mechanism for Alzheimer's Disease
There are a growing number of theories on the mechanisms of Alzheimer's disease. The biochemistry of the brain is very complex and still incompletely mapped, and it is cheaper to theorize than it is to build therapies and test them, so the theorizing is always going to be far more extensive and diverse than ongoing efforts to treat the condition. This is especially true since the consensus efforts based on clearing amyloid from the brain have yet to produce compelling results in trials. It is unclear as to whether this is because it is a difficult challenge, even for the present state of biotechnology, or because it isn't yet the right direction.
This theory focuses on rising levels of oxidative damage to lipids and cholesterols, a process that plays an important role in other age-related disease, such as atherosclerosis. These oxidized molecules can spread throughout the body via the bloodstream, allowing inflammation and generation of reactive oxidizing molecules caused by scattered damaged or senescent cells to contribute to aging everywhere.
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. 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.