Sci. Aging Knowl. Environ., 31 August 2005
Vol. 2005, Issue 35, p. nf69
[DOI: 10.1126/sageke.2005.35.nf69]


Another Knock Against Cholesterol

Artery clogger might promote Alzheimer's disease when damaged

Mitch Leslie

In a cruel double whammy, many patients suffering from Alzheimer's disease (AD) also have atherosclerosis. New work might clarify the connection between the two illnesses. The study reveals that copper and the AD protein {beta} amyloid gang up on cholesterol and spawn brain-injuring compounds. Drugs that separate {beta} amyloid from its metallic accomplice might help forestall neural damage, the results suggest.

AD and atherosclerosis feature plaques, but of different kinds. AD plaques are clumps of {beta}-amyloid protein in the brain (see Detangling Alzheimer's Disease), whereas those of atherosclerosis are fatty deposits in arteries. But diverse evidence links the two killers. For example, high blood cholesterol quantities boost the risk of AD and atherosclerosis. Mice genetically altered to amass {beta} amyloid accumulate more of the protein if they nibble a high-cholesterol diet. Furthermore, {beta}-amyloid clots in AD patients teem with cholesterol. Neuroscientist Ashley Bush of the University of Melbourne in Australia and colleagues have shown that metals naturally found in the brain, such as copper, can latch onto {beta} amyloid, spurring reactions that produce oxidants, destructive chemicals that damage the brains of AD patients (see Mindful of Metal). The researchers wanted to determine whether the copper-{beta}-amyloid tandem would oxidize cholesterol in the brain, a reaction that releases oxidants such as hydrogen peroxide.

In a test tube, copper, {beta} amyloid, and cholesterol produced hydrogen peroxide and oxidized cholesterol. Adding a drug that snatches up copper stymied the reaction, indicating that {beta} amyloid needs the metal to modify cholesterol. Next, the researchers investigated whether {beta} amyloid erodes the cholesterol-rich cell membrane. They steeped neurons in the copper-{beta}-amyloid mixture; the cells leaked and pumped out a protein that heralds their suicide. Dosing the cells with the copper-grabbing compound ameliorated both problems. The researchers also found that brains from AD patients carried almost twice as much oxidized cholesterol as did disease-free brains from people of the same age. Overall, the findings suggest that high blood cholesterol concentrations might encourage AD by providing more targets for {beta} amyloid and copper, says Bush. The work also adds to the evidence that cholesterol-reducing statins and drugs that sop up copper could spare neurons.

The study is significant because it provides "a unified mechanism" that links cardiovascular disease with AD, says cellular and molecular biologist Cheryl Wellington of the University of British Columbia in Canada. Neuropathologist D. Larry Sparks of the Sun Health Research Institute in Sun City, Arizona, says that the experiments reveal an intriguing mechanism, but he questions how much it contributes to AD. {beta} amyloid suppresses cholesterol synthesis, he says, so the protein should limit the amount of cholesterol exposed to attack. The work raises the possibility that {beta} amyloid helps foster cardiovascular disease, says Wellington. {beta} amyloid occurs throughout the body, and it might react with cholesterol in the blood. Further work might reveal ways to keep cholesterol from doubling the misery of the elderly.

August 31, 2005
  1. L. Puglielli et al., Alzheimer disease {beta}-amyloid activity mimics cholesterol oxidase. J. Clin. Invest., 25 August 2005 [e-pub ahead of print]. doi:10.1172/JCI23610[CrossRef][Medline]
Citation: M. Leslie, Another Knock Against Cholesterol. Sci. Aging Knowl. Environ. 2005 (35), nf69 (2005).

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