An interaction between basement membrane and Alzheimer amyloid precursor proteins suggests a role in the pathogenesis of Alzheimer's disease

BACKGROUND: Extracellular matrix proteins (ECMPs) of the basement membrane type, such as the heparan sulfate proteoglycan perlecan, laminin, entactin, collagen IV, and fibronectin are present in and have been implicated in the genesis of amyloids. As in many forms of amyloid, perlecan, laminin, collagen IV, and fibronectin are present in Alzheimer deposits. We have previously demonstrated high-affinity interactions between Alzheimer amyloid precursor proteins (βPP-695, -751, and -770), and perlecan or laminin. With a view to examining our hypothesis that βPP:ECMP interactions are involved in Alzheimer's amyloidogenesis, additional studies have now been performed examining the interactions of the βPPs with entactin, fibronectin, and collagen IV, the influence each of the ECMPs has on the binding of the others to βPPs, and the effect of βPPs on interactions among the various ECMPs. EXPERIMENTAL DESIGN: A modified solid-phase enzyme-linked immunosorbent assay was used to assess the binding of the various ECMPs to the βPPs. One element was immobilized on plastic, and another element, operationally defined as a ligand, was incubated in solution at various concentrations over the immobilized protein. To evaluate the effect of one ECMP on the binding of other ECMPs to βPP, the DPP was immobilized and the binding of the 'ligand' ECMP was assessed in the presence of a single concentration of a second 'competitor' ECMP. Similarly, in evaluating the effect of βPPs on the binding of ECMPs 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 βPP 'competitor.' RESULTS: As in the case of perlecan and laminin, each of the ECMPs bound to the βPPs with high affinity (K(d) values in the nanomolar range). The binding of entactin to βPPs was stimulated by collagen IV but was markedly inhibited by laminin, perlecan, and fibronectin. Conversely, the presence of entactin inhibited the binding of perlecan, laminin, and fibronectin to βPPs. Moreover, the presence of βPPs usually interfered with the binding of ECMPs to each other. Generally, in all binding assays, βPP- 751 and -770, behaved in similar ways, but βPP-695, the brain-specific form, exhibited unique characteristics. CONCLUSIONS: These binding data may reflect the normal interactions of βPPs with ECMPs. However, the fact that βPPs interfere with the normal interactions between ECMPs themselves, a process that spontaneously generates a basement membrane, suggests that aspects of ECMP:βPP binding may be a pathologic part of the amyloidogenic process in Alzheimer's disease.