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.
Division of Neuropathology, Case Western Reserve University, Cleveland, Ohio 44106.
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LeBlanc
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Gambetti
D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism; D017931:DNA Primers; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008247:Lysosomes / Q000378:metabolism; D008969:Molecular Sequence Data; D008970:Molecular Weight; D016133:Polymerase Chain Reaction; D015183:Restriction Mapping; D014162:Transfection; D014407:Tumor Cells, Cultured
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D017931:DNA Primers