β-Amyloid (Aβ) causes detachment of N1E-115 neuroblastoma cells by acting as a scaffold for cell-associated plasminogen activation

A major component of neuritic plaques in brain tissue of Alzheimer's disease patients is the β-amyloid peptide (Aβ). Accumulation of Aβ has been associated with increased neuronal cell death and cognitive decline. We have previously shown that amyloid peptides like Aβ bind tissue-type plasminogen activator (tPA) and stimulate plasmin production. Here we investigated how Aβ regulates plasmin formation by N1E-115 neuroblastoma cells and the effects of Aβ-mediated plasmin formation on cell attachment and cell survival. We find that Aβ induces excessive cell-associated plasmin generation that causes cell detachment. Cell detachment is inhibited by carboxypeptidase B (CPB), an enzyme that blocks plasmin formation by cleaving off C-terminal lysine residues. Plasmin and CPB control Aβ-induced cell detachment independently of direct effects on cell viability. Aβ40 as well as oligomeric and fibrillar forms of Aβ42 stimulated tPA-mediated plasminogen activation and cell detachment. Our results suggest that plasmin-mediated cell detachment could contribute to the pathological effects of Aβ in diseased brain.