Aberrant proteolysis of the beta-amyloid precursor protein in familial Alzheimer's disease lymphoblastoid cells.

Abstract

Lymphoblastoid cells from patients with early-onset and late-onset familial Alzheimer's disease showed increased expressions of beta-amyloid precursor mRNA and protein as well as interleukin-1 and alpha 1-antichymotrypsin protein. Early-onset and late-onset familial Alzheimer's disease cells had greater production of 16-kDa beta-amyloid C-terminal preamyloid peptides than did normal cells. A pulse-chase experiment indicated that aberrant processing of this peptide resulted in its abnormal accumulation. Furthermore, the peptide prepared from early-onset familial Alzheimer's disease cells using formic acid could be separated into four discrete fragments. The N-terminal amino acid sequencing of each fragment indicated that the 16-kDa peptide was generated by cleavage, principally at the 30 amino acids N-terminal to beta-amyloid. Both the enhanced synthesis and aberrant processing of the beta-amyloid precursor protein, therefore, are basic processes associated with familial Alzheimer's disease lymphoblastoid cells.