Signature Amyloid beta Profiles Are Produced by Different gamma-Secretase Complexes

Background: -Secretase complexes generate amyloid- (A) in Alzheimer disease. Results: A profiles of the four -secretase complexes expressed in humans show that PSEN regulates total peptide levels and the A(38) pathway, whereas APH1 affects mainly the efficiency of the carboxypeptidase-like activity. Conclusion: -Secretase subunit composition regulates A generation. Significance: These intrinsic differences could be used to advance AD therapeutic development.

-Secretase complexes are involved in the generation of amyloid- (A) in the brain. Therefore, -secretase has been proposed as a potential therapeutic target in Alzheimer disease (AD). Targeting -secretase activity in AD requires the pharmacological dissociation of the processing of physiological relevant substrates and the generation of toxic A. Previous reports suggest the differential targeting of -secretase complexes, based on their subunit composition, as a valid strategy. However, little is known about the biochemical properties of the different complexes, and key questions regarding their A product profiles should be first addressed. Here, we expressed, purified, and analyzed, under the same conditions, the endopeptidase and carboxypeptidase-like activities of the four -secretase complexes present in humans. We find that the nature of the catalytic subunit in the complex affects both activities. Interestingly, PSEN2 complexes discriminate between the A(40) and A(38) production lines, indicating that A generation in one or the other pathway can be dissociated. In contrast, the APH1 subunit mainly affects the carboxypeptidase-like activity, with APH1B complexes favoring the generation of longer A peptides. In addition, we determined that expression of a single human -secretase complex in cell lines retains the intrinsic attributes of the protease while present in the membrane, providing validation for the in vitro studies. In conclusion, our data show that each -secretase complex produces a characteristic A signature. The qualitative and quantitative differences between different -secretase complexes could be used to advance drug development in AD and other disorders.