Switched Aß43 generation in familial Alzheimer's disease with presenilin 1 mutation.

Presenilin (PS) with a genetic mutation generates abundant ß-amyloid protein (Aß) 43. Senile plaques are formed by Aß43 in the cerebral parenchyma together with Aß42 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 Aß generation by γ-secretase, we reassessed the levels of Aßs in the cerebrospinal fluid (CSF) of FAD participants. While low levels of Aß38, Aß40, and Aß42 were generated in the CSF of FAD participants, the levels of Aß43 were unchanged in some of them compared with other participants. We sought to investigate why the level of Aß43 was unchanged in FAD participants. These characteristics of Aß generation were observed in the γ-secretase assay in vitro using cells, which express FAD mutations in PS1. Aß38 and Aß40 generation from their precursors, Aß42 and Aß43, was decreased in PS1 mutants compared with wild-type (WT) PS1, as observed in the CSF. Both the ratios of Aß38/Aß42 and Aß40/Aß43 in PS1 mutants were lower than those in the WT. However, the ratio of Aß43/amyloid precursor protein intracellular domain (AICD) increased in the PS1 mutants in an onset age dependency, while other Aß/AICD ratios were decreased or unchanged. Importantly, liquid chromatography-mass spectrometry found that the generation of Aß43 was stimulated from Aß48 in PS1 mutants. This result indicates that PS1 mutants switched the Aß43 generating line, which reflects the level of Aß43 in the CSF and forming senile plaques.