Switched Aβ43 generation in familial Alzheimer's disease with presenilin 1 mutation

Presenilin (PS) with a genetic mutation generates abundant beta-amyloid protein (A beta) 43. Senile plaques are formed by A beta 43 in the cerebral parenchyma together with A beta 42 at middle ages. These brains cause the early onset of Alzheimer's disease (AD), which is known as familial Alzheimer's disease (FAD). Based on the stepwise processing model of A beta generation by gamma-secretase, we reassessed the levels of A beta s in the cerebrospinal fluid (CSF) of FAD participants. While low levels of A beta 38, A beta 40, and A beta 42 were generated in the CSF of FAD participants, the levels of A beta 43 were unchanged in some of them compared with other participants. We sought to investigate why the level of A beta 43 was unchanged in FAD participants. These characteristics of A beta generation were observed in the gamma-secretase assay in vitro using cells, which express FAD mutations in PS1. A beta 38 and A beta 40 generation from their precursors, A beta 42 and A beta 43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of A beta 38/A beta 42 and A beta 40/A beta 43 in PS1 mutants were lower than those in the WT. However, the ratio of A beta 43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other A beta/AICD ratios were decreased or unchanged. Importantly, liquid chromatography-mass spectrometry found that the generation of A beta 43 was stimulated from A beta 48 in PS1 mutants. This result indicates that PS1 mutants switched the A beta 43 generating line, which reflects the level of A beta 43 in the CSF and forming senile plaques.