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

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Abstract
Release of amyloid β (Aβ) from the amyloid precursor protein (APP) requires cleavages by β- and γ-secretases and plays a crucial role in Alzheimer’s disease (AD) pathogenesis. Missense mutations in the APP gene causing familial AD are clustered around the β-, α- and particular γ-secretase cleavage sites. We systematically compare in primary neurons the effect on APP processing of a series of clinical APP mutations (two of which not characterized before) located in close proximity to the γ-secretase cleavage site. We confirm and extend previous observations showing that all these mutations (T714I, V715M, V715A, I716V, V717I and V717L) affect γ-secretase cleavage causing an increased relative ratio of Aβ42 to Aβ40. Taking advantage of these extended series of APP mutations 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-terminal fragments. However, it is unlikely that these fragments contribute significantly to the disease process.

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