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.
Janciauskiene
S
S
Institute for Structural Biology and Drug Discovery, Virginia Commonwealth University, Richmond 23298-0133, USA.
Wright
H T
HT
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