The molecular pathways by which beta-amyloid protein (A beta) induces neurotoxicity in vitro are unknown. We report that cultured hippocampal neurons exhibiting immunoreactivity for the calcium binding protein calretinin are relatively resistant to degeneration resulting from exposure to either beta 25-35 or beta 1-42. These findings suggest that intrinsic characteristics of calretinin cells, possibly including enhanced calcium buffering capacity, underlie the resistance of these cells to A beta toxicity in vitro and perhaps similar insults in Alzheimer's disease.