Localization of presenilin-2 (PS-2), a transmembrane protein implicated in early onset familial Alzheimer's disease, was examined in the brains of 30 cynomolgus monkeys aged 4 to 36 years. Anti-PS-2 antibody N20, which recognizes PS-2 amino acid residues 2-20, and anti-PS-2 antibody C20, which recognizes PS-2 amino acid residues 535-554, stained mainly the cytoplasm of large pyramidal neurons and large neurites. This finding was also confirmed by double immunohistochemical investigations using N20 or C20 and anti-NeuN antibody. In the brain of the oldest monkey, swollen neurites containing senile plaques were immunostained with C20, but not with N20. Western blot analyses of microsomal fractions isolated from the brains of three adult monkeys revealed that much less PS-2 was present compared to presenilin-1 (PS-1). Age-related assessment of PS-2 in brain homogenates from young and adult monkeys showed that PS-2 levels and PS-2 subcellular localization were unchanged with increasing age. Because PS-2 expression was much less robust than that of PS-1, we conclude that PS-2 mainly localizes to large neurons and does not show so drastic age-related changes as PS-1.