Pathogenic APP mutations near the gamma-secretase cleavage site differentially affect A beta secretion and APP C-terminal fragment stability

Release of amyloid beta (A beta) from the amyloid precursor protein (APP) r equires cleavages by beta- and gamma -secretases and plays a crucial role i n Alzheimer's disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the beta-, alpha- and particular gamma -secretase cleavage sites. We systematically compare in primary neuro ns the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the gamma -secretase cleavage site. We confirm and extend previous observations showi ng that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) a ffect gamma -secretase cleavage causing an increased relative ratio of A be ta 42 to A beta 40. Taking advantage of these extended series of APP mutati ons we were able to demonstrate an inverse correlation between these ratios and the age at onset of the disease in the different families In addition, a subset of mutations caused the accumulation of APP C-terminal fragments indicating that these mutations also influence the stability of APP C-termi nal fragments. However, it is unlikely that these fragments contribute sign ificantly to the disease process.