The processing of β-amyloid precursor protein (APP) is considered critical for understanding the pathogenesis of Alzheimer's disease (AD). To elucidate the significance of APP processing enzyme, we studied immunohistochemically the distribution of APP-processing protease (human carboxypeptidase B: HBCPB) in the normal control brains and AD brains, using anti-C14 antibody which recognizes C-terminal 14 amino acids of HBCPB. In the control brains, intense and diffuse C14-immunoreactivity was observed in the cytoplasm of pyramidal neurons of the hippocampus. Moderate immunoreactivity was found in the cortical and subcortical neurons. In AD brains, C14-immunoreactivity was markedly decreased in the brain regions examined except for the brain stem and cerebellum. However, HBCPB was shown to be colocalized with β-amyloid protein (Aβ) in neuritic plaques. In addition, neuritic plaques included C14-immunoreactive microglia/macrophages. Our present studies indicate that the expression of a novel APP-processing protease is impaired in AD brains and may suggest the possible role of HBCPB in the pathogenesis of AD.