Inflammation, antichymotrypsin, and lipid metabolism: autogenic etiology of Alzheimer's disease.
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.
Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond 23298-0133, USA.
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Janciauskiene
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Wright
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D006801:Humans; D007249:Inflammation; D050356:Lipid Metabolism; D000514:alpha 1-Antichymotrypsin / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000514:alpha 1-Antichymotrypsin