Substrate-bound beta-amyloid peptides inhibit cell adhesion and neurite outgrowth in primary neuronal cultures

Accumulation of the beta-amyloid protein (A beta) in the brain is an import ant step in the pathogenesis of Alzheimer's disease. However, the mechanism of A beta toxicity remains unclear. A beta can bind to the extracellular m atrix, a structure that regulates adhesive events such as neurite outgrowth and synaptogenesis. The binding of A beta to the extracellular matrix sugg ests that A beta may disrupt cell-substrate interactions. Therefore, the ef fect of substrate-bound A beta on the growth of isolated chick sympathetic and mouse cortical neurons was examined. A beta 1-40 and A beta 1-42 had do se-dependent effects on cell morphology. When tissue culture plates were co ated with 0.1-10 ng/well A beta, neurite outgrowth increased. Higher amount s of A beta peptides (greater than or equal to 3 mu g/well) inhibited outgr owth. The inhibitory effect was related to aggregation of the peptide, as p reincubation of A beta 1-40 for 24 h at 37 degrees C (a process known to in crease amyloid fibril formation) was necessary for inhibition-of neurite ou tgrowth. A beta 29-42, but not A beta 1-28, also inhibited neurite outgrowt h at high concentrations, demonstrating that the inhibitory domain is locat ed within the hydrophobic C-terminal region. A beta 1-40, A beta 1-42, and A beta 29-42 also inhibited cell-substrate adhesion, indicating that the ef fect on neurite outgrowth may have been due to inhibition of cell adhesion. The results suggest that accumulation of A beta may disrupt cell-adhesion mechanisms in vive.