AN INTERACTION BETWEEN BASEMENT-MEMBRANE AND ALZHEIMER AMYLOID PRECURSOR PROTEINS SUGGESTS A ROLE IN THE PATHOGENESIS OF ALZHEIMERS-DISEASE

BACKGROUND: Extracellular matrix proteins (ECMPs) of the basement memb rane type, such as the heparan sulfate proteoglycan perlecan, laminin, entactin, collagen IV, and fibronectin are present in and have been i mplicated in the genesis of amyloids. As in many forms of amyloid, per lecan, laminin, collagen IV, and fibronectin are present in Alzheimer deposits. We have previously demonstrated high-affinity interactions b etween Alzheimer amyloid precursor proteins (beta PP -695, -751, and - 770), and perlecan or laminin. With a view to examining our hypothesis that beta PP:ECMP interactions are involved in Alzheimer's amyloidoge nesis, additional studies have now been performed examining the intera ctions of the beta PPs with entactin, fibronectin, and collagen TV, th e influence each of the ECMPs has on the binding of the others to beta PPs, and the effect of beta PPs on interactions among the various ECM Ps. EXPERIMENTAL DESIGN: A modified solid-phase enzyme-linked immunoso rbent assay was used to assess the binding of the various ECMPs to the beta PPs. One element was immobilized on plastic, and another element , operationally defined as a ligand, was incubated in solution at vari ous concentrations over the immobilized protein. To evaluate the effec t of one ECMP on the binding of other ECMPs to beta PP, the beta PP wa s immobilized and the binding of the ''ligand'' ECMP was assessed in t he presence of a single concentration of a second ''competitor'' ECMP. Similarly, in evaluating the effect of beta PPs on the binding of ECM Ps to each other, one ECMP was immobilized and the binding of a second ECMP ''ligand'' was assessed in the presence of a fixed concentration of beta PP ''competitor.'' RESULTS: As in the case of perlecan and la minin, each of the ECMPs bound to the beta PPs with high affinity (K-d values in the nanomolar range). The binding of entactin to beta PPs w as stimulated by collagen TV but was markedly inhibited by laminin, pe rlecan, and fibronectin. Conversely, the presence of entactin inhibite d the binding of perlecan, laminin, and fibronectin to beta PPs. Moreo ver, the presence of beta PPs usually interfered with the binding of E CMPs to each other. Generally, in all binding assays, beta PP-751 and -770, behaved in similar ways, but beta PP-695, the brain-specific for m, exhibited unique characteristics. CONCLUSIONS: These binding data m ay reflect the normal interactions of beta PPs with ECMPs. However, th e fact that beta PPs interfere with the normal interactions between EC MPs themselves, a process that spontaneously generates a basement memb rane, suggests that aspects of ECMP:PPP binding may be a pathologic pa rt of the amyloidogenic process in Alzheimer's disease.