Processing of Alzheimer's disease-associated β-amyloid precursor protein

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Abstract
Studies were undertaken on the processing of Alzheimer's disease-associated β-amyloid precursor protein in normal cultured human fibroblasts and a human neuroblastoma cell line. Major differences in processing between the secreted and intracellular forms of the precursor were found. The intracellular form appears to undergo amino-terminal processing yielding many smaller fragments, whereas the secreted from does not show any further proteolytic cleavage after its release from the cell surface. In pulse-chase experiments, antibodies to the A4 region immunoprecipitated bands of Mr=92,000−128,000, which represent the intact precursor; several smaller intracellular fragments of Mr=70,000–72,000, 55,000, 33,000 and 6,000 also immunoprecipitated with this antibody. The Mr=6,000 band cleared from the cell very quickly and is postulated to be the A4-carring remnant of the secreted protein. The data show that a fragment of Mr=33,000, which includes the A4 region, is one stable processed end-product of the intracellular precursor protein. It is possible that different posttranslational modifications are the signals responsible for the differences in processing between the secreted and intracellular amyloid precursor protein.