IN-VITRO GROWTH OF ALZHEIMERS-DISEASE BETA-AMYLOID PLAQUES DISPLAYS FIRST-ORDER KINETICS

A Salient pathological feature of Alzheimer's disease (AD) is the pres ence of amyloid plaques in the brains of affected patients. The plaque s are predominantly composed of human beta-amyloid peptide (A beta). A lthough the aggregation of synthetic A beta has been extensively studi ed, the mechanism of AD plaque growth is poorly understood. In order t o address this question, we used an in vitro model of plaque growth to determine if assembly or aggregation of A beta is required for deposi tion. Labeled A beta at physiological concentrations readily deposited onto both neuritic and diffuse plaques and cerebrovascular amyloid in unfixed AD brain tissue, whereas essentially no deposition was detect ed in tissue without preformed amyloid. Using this in vitro model of p laque growth, the kinetics of A beta deposition onto plaques was exami ned in two independent but complementary systems. Intact sections of u nfixed AD brain cortex (analyzed by autoradiographic densitometry) all owed definitive morphological analysis of the site of deposition, whil e homogenates of the same tissue (analyzed by radioisotope counting) a llowed precise quantitation of deposition over a wide range of conditi ons. Essentially identical results were obtained for both systems. Gro wth of preexisting tissue plaques by deposition of A beta was found to follow first-order dependence on A beta concentration and exhibited a pH optimum of 7. In sharp contrast, A beta aggregation in the absence of template follows higher order kinetics and shows a pH optimum of 5 . On the basis of criteria of kinetic order, pH dependence, and struct ure-activity relationships, we conclude that aggregation of A beta (te mplate-independent initial nidus formation) and deposition of A beta ( template-dependent subsequent plaque growth) are fundamentally distinc t biochemical processes. The process of plaque growth and maturation b y A beta deposition may be an important target for therapeutic interve ntion to block the progression of AD.