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SAGE KE Bulletin Board

Direct link between Abeta and cholesterol metabolism

21 September 2005

Dietmar R. Thal

Comment on Puglielli et al. Alzheimer disease beta-amyloid activity mimics cholesterol oxidase. J Clin Invest (2005) 115: 2556-63

Alzheimer’s disease (AD) is characterized by the deposition of the amyloid beta-protein (Abeta) and the generation of neurofibrillary tangles in the brain. In addition, to these changes, oxidation of cholesterol has been proposed to be a pathogenic event in AD. Puglielli et al. show that Abeta:Cu2+ complexes oxidize cholesterol selectively at the C-3 hydroxyl group, produce 4- cholesten-3-one and, thereby, mimic the activity of a cholesterol oxidase. In so doing, this study provides evidence that the production of Abeta and its function as cholesterol oxidase can be responsible for changes in the cerebral cholesterol metabolism. The oxidation product 4-cholesten-3-one contributes to neuronal damage. The authors speculate that the reduction of cholesterol, e.g. by the use of statins, reduces the cholesterol in the brain and, in so doing, reduces the substrate for Abeta:Cu2+ cholesterol oxidase. The resulting reduction of 4-cholesten-3-one will protect from 4- cholesten-3-one mediated neurodegeneration. This study points to a direct link between Abeta, cerebral cholesterol metabolism, and neurodegeneration. Such an Abeta induced neurodegeneration mediated by 4-cholesten-3-one may be started either by increased levels of Abeta leading to an increased cholesterol oxidase activity, and finally to alterations in cerebral cholesterol metabolism, or by increased cholesterol levels providing high levels of substrate for Abeta:Cu2+ cholesterol oxidase complex leading to the production of increased levels of 4-cholesten-3-one. Following the first possibility the increase of cholesterol in AD patients would be the result from compensatory cholesterol production which in turn provides further substrate for Abeta:Cu2+ cholesterol oxidase

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Science of Aging Knowledge Environment. ISSN 1539-6150