Evidence that the Amyloid-β Protein Precursor Intracellular Domain, AICD, Derives From β-Secretase-Generated C-Terminal Fragment

One of the major pathological hallmarks of brains affected with Alzheimer's disease (AD) is the senile plaque, an extracellular deposit mainly composed of a set of highly insoluble peptides of various lengths (39-43 amino acids) referred to as amyloid-beta (A beta) peptides. A beta peptides are derived from combined proteolytic cleavages undergone on the amyloid-beta protein precursor (A beta PP) by a set of enzymes called secretases. Several lines of anatomical and biological evidence suggest that A beta peptides would not account for all pathological stigmata and molecular dysfunctions taking place in AD. In amyloidogenic and non-amyloidogenic pathways, A beta PP first undergoes beta- or alpha-secretases-mediated cleavages yielding C99 and C83, respectively. These two membrane-embedded C-terminal fragments are both potential targets of subsequent gamma-secretase-mediated proteolysis. The latter cleavage not only generates either p3 or A beta peptides but similarly gives rise to an A beta PP IntraCellular Domain (AICD fragment) that could modulate the transcription of several genes linked to AD pathology. It is therefore striking that AICD theoretically derives from both amyloidogenic and non-amyloidogenic A beta PP processing pathways. Here we show that AICD predominantly derives from C99 by means of recombinant substrates and transiently transfected cells expressing C99. Our data suggest a preferred pathogenic pathway for AICD production and suggests that this fragment, in addition to C99 and A beta peptides, could contribute to AD pathology.