Familial Alzheimer's Disease Mutations in Presenilin 1 Do Not Alter Levels of the Secreted Amyloid-Protein Precursor Generated by β-Secretase Cleavage

Alzheimer's disease (AD) is an insidious and progressive disease with a genetically complex and heterogenous etiology. More than 200 fully penetrant mutations in the amyloid beta-protein precursor (APP), presenilin 1 (or PSEN1), and presenilin 2 (PSEN2) have been linked to early-onset familial AD (FAD). 177 PSEN1 FAD mutations have been identified so far and account for more than similar to 80% of all FAD mutations. All PSEN1 FAD mutations can increase the A beta 42:A beta 40 ratio with seemingly different and incompletely understood mechanisms. A recent study has shown that the 286 amino acid N-terminal fragment of APP (N-APP), a proteolytic product of beta-secretase-derived secreted form of APP (sAPP beta), could bind the death receptor, DR6, and lead to neurodegeneration. Here we asked whether PSEN1 FAD mutations lead to neurodegeneration by modulating sAPP beta levels. All four different PSEN1 FAD mutations tested (in three mammalian cell lines) did not alter sAPP beta levels. Therefore PS1 mutations do not appear to contribute to AD pathogenesis via altered production of sAPP beta.