THE AMYLOID PEPTIDE OF ALZHEIMERS-DISEASE IS NOT PRODUCED BY INTERNALINITIATION OF TRANSLATION GENERATING C-TERMINAL AMYLOIDOGENIC FRAGMENTS OF ITS PRECURSOR

The molecular mechanisms of the amyloid peptide (A beta) production fr om the amyloid precursor protein (APP) remain unclear and it has been suggested that initiation of translation at methionine 596, which imme diately precedes the A beta sequence, could generate soluble amyloidog enic fragments. We show that the amyloid peptide is actually produced by expression of the C-terminal 100 residues of the APP, using methion ine 596 as an initiation codon. However, the amyloid peptide is no lon ger detectable when a stop codon is introduced in the APP mRNA, before the A beta coding region. These results strongly suggest that A beta is produced by degradation of APP and not by local translation of its mRNA.