EXTRACELLULAR-MATRIX REGULATES THE AMOUNT OF THE BETA-AMYLOID PRECURSOR PROTEIN AND ITS AMYLOIDOGENIC FRAGMENTS

We have studied the influence of the extracellular matrix (ECM) on the amount of beta-amyloid precursor protein (APP) and C-terminal amyloid -bearing fragments in 3T3 fibroblasts. After incubation with ECM compo nents, the cellular APP content of 3T3 cells changed. Besides, differe nt substrata including collagen, fibronectin, laminin, vitronectin, an d heparin, determined changes in the amount of a C-terminal 22 kDa-fra gment. The regulation of amyloidogenic fragments by the ECM was transi ent; in fact, when 3T3 cells were plated on tissue culture dishes coat ed with collagen or vitronectin, maximal levels of the 22 kDa fragment were observed 12 h after plating; in the presence of fibronectin, the maximum level of the amyloidogenic fragment was obtained 36 h after p lating. These results indicate that the ECM modulates in a transient w ay the generation of APP-derived polypeptides containing the amyloid-b eta-peptide (A beta). The ECM does not have a generalized effect on 3T 3 fibroblasts, because no significant differences in cell attachment, growth rate, whole-cell polypeptide pattern, beta(1) integrin and a-tu bulin levels were observed on cells grown on various matrix proteins. Laminin, collagen, and heparin also influence the level of an amyloido genic fragment of 35 kDa in Neuro 2A neuronal cells, without a signifi cant change in the neuronal marker acetylcholinesterase. In this case, however, a long-lasting response to ECM molecules was observed. These observations provide evidence that ECM molecules influence APP biogen esis, including the generation of amyloidogenic fragments containing t he A beta peptide. Our studies might prove significant to understand t he localized increment of beta-amyloid deposition in selected areas of the brain of Alzheimer's patients. (C) 1996 Wiley-Liss, Inc.