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FEBS Lett. 2009 May 6;583(9):1403-8. doi: 10.1016/j.febslet.2009.04.014. Epub 2009 Apr 17.

An alternative spliced mouse presenilin-2 mRNA encodes a novel gamma-secretase inhibitor.

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Department of Neurobiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.


The gamma-secretase, composed of presenilin-1 (PS1) or presenilin-2 (PS2), nicastrin (NCT), anterior pharynx-defective phenotype 1 (APH-1), and PEN-2, is critical for the development of Alzheimer's disease (AD). PSs are autoproteolytically cleaved, producing an N-terminal fragment (NTF) and a hydrophilic loop domain-containing C-terminal fragment. However, the role of the loop domain in the gamma-secretase complex assembly remains unknown. Here, we report a novel PS2 isoform generated by alternative splicing, named PS2beta, which is composed of an NTF with a hydrophilic loop domain. PS2beta disturbed the interaction between NCT and APH-1, resulting in the inhibition of amyloid-beta production. We concluded that PS2beta may inhibit gamma-secretase activity by affecting the gamma-secretase complex assembly.

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