The March 19 2004 online early edition of the Proceedings of the National Academy of Sciences (www.pnas.org) published an article which proposes a new theory concerning the cause of Alzheimer’s disease. The authors, from The Scripps Research Institute, suggest that Alzheimer’s disease is a result of inflammation which leads to the formation of abnormal metabolites from normal brain molecules. These metabolites modify brain amyloid beta proteins, causing them to misfold and accumulate as plaques and fibrils that are characteristic of the disease and which cause the loss of neurons. The inflammatory process can be caused by infections or other factors that can precede the onset of the disease by years.
Alzheimer’s disease is one of several disease caused by protein misfolding. In some of these diseases mutations that cause misfolding have been identified, but with the exception of a rare form of familial Alzheimer’s disease, the cause in 95 percent of cases of the disease was unknown. This suggests a more common cause, and the Scripps researchers set out to find it.
In previous research, two of the current paper’s authors revealed how inflammation can lead to the formation of reactive oxygen species such as ozone, which can damage cholesterol and other molecules in the body. They found that during inflammation, ozone reacts with normal metabolites to produce toxic compounds, two of which they have labeled "atheronals." They suggested that these compounds are involved in atherosclerosis because atheronals have been identified in atherosclerotic plaques removed from patients with the disease.
In the current study, Scripps research professor Jeffery W Kelly and colleagues examined the brains of autopsied patients with Alzheimer’s disease and compared them to normal brains, finding evidence of atheronals in both groups. The researchers believe that a precipitating event in the presence of atheronals, such as a the inflammation caused by a head injury, may propagate protein misfolding and the buildup of fibrils.
The team also found that atheronals and lipid oxidation products accelerate the misfolding of amyloid beta in vitro. Kelly and colleagues suggest that inflammation could create conditions in which cholesterol and fats react with ozone and other inflammatory compounds to produce abnormal metabolites, which modify the folding of amyloid beta protein, leading to misfolding of other unmodified amyloid beta proteins, which eventually results in Alzheimer's disease.
Dr Kelly commented, "If a certain inflammatory metabolite or family of metabolites confers risk later in life, then we need to know this, and we need to attack the problem.”
Source: Life Extension Foundation (online at www.lef.org).