Production of Alzheimer 4kDa beta-amyloid peptide requires the C-terminal cytosolic domain of the amyloid precursor protein.

Amyloid precursor protein (APP) is metabolized through at least three pathways: the constitutive secretory pathway, the endosomal-lysosomal pathway and the 4-kDa A beta-producing pathway. The 4-kDa A beta (4 kDa A beta)-producing pathway which may play a primary role in the pathogenesis of Alzheimer's disease (AD) is presently unknown. In the present paper, we examine the production of the 4 kDa A beta in K562 lymphoid cells transfected with a truncated APP695 construct (APP delta 652-695) encoding an APP which lacks the cytosolic C-terminal domain except the four N-terminal amino acids, KKKQ. The APP delta 652-695-transfected cells (APP delta 652-695 cells) do not secrete 4 kDa A beta compared to APP 695-transfected cells (APP695 cells). Moreover, while the APP delta 652-695 and APP695 cells secrete equivalent levels of sAPP, the APP delta 652-695 cells accumulate less APP intracellularly than the APP695 cells. These results reveal that in the K562 cells (1), the last 43 amino acid residues at the C-terminus of APP are important in targeting APP through the 4 kDa A beta producing pathway and (2) processing of APP into 4 kDa A beta is independent of the known secretase pathway.