The Role of the Extracellular Matrix in Regulating the Function of the Amyloid Protein Precursor of Alzheimer’s Disease

Studies on rare autosomal dominant mutations affecting the amyloid protein precursor (APP) gene have highlighted the importance of APP in the pathogenesis of Alzheimer’s disease (AD). However, the link between the observed changes in APP processing and the pathogenic mechanism remains unclear. We have examined the possibility that disruption of the normal function of APP may underlie the neurodegenerative changes. The presence of APP in cells important for tissue repair following injury (platelets and fibroblasts) and the observation that APP expression is increased during early development suggest that APP has a function in cell growth and regeneration. We have found that APP promotes neurite outgrowth from PC 12 cells when added directly to the cell growth medium. APP was also found to stimulate neurite outgrowth from primary cultures of central and peripheral neurons. The effect of APP on neurite outgrowth from primary cultures was most marked when APP was in substratum-bound form, and was dependent upon the presence of heparan sulphate proteoglycans (HSPGs). The binding of APP to HSPGs in vitro may mimic certain aspects of the binding of APP to the extracellular matrix (ECM) in vivo. Thus the interaction of secreted APP with ECM may be an important step in the activation of APP. Basement membrane ECM regulates the guidance of neurites towards their targets in the developing nervous system. Major protein components of ECM include collagen, laminin and the HSPGs, which have all been reported to interact with APP. APP interacts with HSPGs by binding to the heparan sulphate moieties. APP also binds heparin, an analogue of heparan sulphate. Molecular modelling and site-directed mutagenesis experiments suggest that at least one heparin-binding site exists close to the N-terminus of APP between amino acid residues 96 and 110. A peptide homologous to this region of APP blocked the action of APP on neurite outgrowth.