Characterization by radiosequencing of the carboxyl-terminal derivatives produced from normal and mutant amyloid β protein precursors

Tobun T. Cheung, Jorge Ghiso, Mikio Shojif, Xiao Dan Cai, Todd Golde, Samuel Gandy, Bias Frangione, Steven Younkin

Research output: Contribution to journalArticlepeer-review

24 Scopus citations


The 39-43 amino acid (∼ kD) amyloid β protein (Aβ deposited as amyloid Alzheimer's disease is an internal peptide beginning 99 residues from the COOH end of a much larger amyloid fiprotein precursor (βAPP). In cultured cells, normal processing of the PAPP produces ∼8.7, ∼9.6, ∼10.9, and ∼ 11.4 kD COOH-terminal derivatives that appear to contain all or part of the Aβ domain. In this study, we metabolically labeled transfected human neuroblastoma (Ml 7) cells with PH] phenylalanine plus (35SJmethionine and then radiosequenced the immunopre-cipitated COOH-terminal βAPP derivatives taking advantage of the fact that the Aβ has phenylalanines at positions 4, 19, and 20, and a single methionine at position 35. Our analysis of the derivatives produced by transfected Ml 7 cells expressing βAPP695 confirms that the ∼8.7 kD COOH-terminal derivative begins at Aβ17 and indicates that the ∼9.6 and ∼10.9 kD derivatives begin at Aβ10 and Aβ4 respectively. Significantly, we find that the 11.4 kD derivative begins at APr Thus normal PAPP processing produces a potentially amyloidogenic COOH-terminal derivative that has the Aβ domain intact at its amino terminus. We have previously shown that cells expressing βAPPWL, a mutant linked to familial Alzheimer's disease, produce an increased amount of the 11.4 kD COOH-terminal derivative and secrete more Aβ Radiosequencing of these derivatives showed that the ANL mutant is cleaved at the same location as wild type βAPP producing an 11.4 kD COOH-terminal derivative and Aβ that both begin at Aβ Thus the ANL mutation appears to accelerate a cleavage that releases an 11.4 kD COOH-terminal derivative identical to that normally produced from wild type PAPP, and it appears that this 11.4 kD derivative is further processed to release excess Aβ.

Original languageEnglish (US)
Pages (from-to)30-38
Number of pages9
Issue number1
StatePublished - 1994


  • Alzheimer's disease
  • Amyloid beta protein
  • Amyloid protein precursor
  • Familial alzheimer's disease
  • Sequencing

ASJC Scopus subject areas

  • Internal Medicine


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