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Bioessays. 1998 Dec;20(12):1039-46.

Inflammation, antichymotrypsin, and lipid metabolism: autogenic etiology of Alzheimer's disease.

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1
Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond 23298-0133, USA.

Abstract

Alzheimer's disease is a multifactor pathology, some of whose causes have been inferred from genetic studies, primarily of associated early-onset cases. Much evidence implicates the A beta amyloid peptide as a neurotoxic agent, with chronic inflammation as an accompanying physiological contributor to the disease. The two central questions of how A beta kills neurons and of the autogenic basis of disease remain unanswered. We hypothesize that specific interactions of A beta with the inflammatory serpin, alpha 1-antichymotrypsin, abolish the serpin proteinase inhibitor activity and stimulate formation of the neurotoxic fibrillar form of A beta. Further, the fibrillar A beta interacts with specific cell surface receptors, prompting its own biosynthesis and disrupting cellular cholesterol metabolism. These molecular and cellular interactions autogenically sustain the processes of A beta formation, fibrillization, and receptor interaction, the last of which culminates in neuronal death through disruption of cholesterol metabolism.

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