![]() Importantly, it does not induce Notch-related side effect in wild-type (WT) mouse model 22, 24. MRK-560 leads to reduced Aβ production in the brain. In this way, Notch signaling may be preserved through PS2 cleavage 21.Ī small molecule compound, N-4-(2,5-difluorophenyl) cyclohexyl]-1,1,1-trifluoromethanesulfonamide (known as MRK-560), is a PS1-selective GSI that shows 37 folds higher suppression of the PS1-complex over PS2 22, 23. PS1-selective inhibitors, which target aberrant cleavages of APP by PS1 mutants, may thus serve as a candidate for the treatment of AD patients bearing PS1 pathogenic mutations. PS1 hosts more than 80% of AD pathogenic mutations, and PS2 and APP carry the rest of the identified mutations ( ). Interestingly, they release nearly equal amount of AICD and Notch intracellular domain (NICD) 20. The PS1- and PS2 complexes contribute to ~80% and 20% of Aβ production, respectively 2. The PS1-complex (short for PS1-containing γ-secretase) is more catalytically active for Aβ production, as seen in a cell-based assay as well as PS1/PS2 knockout mice 19. γ-Secretases that contain different isoforms of each subunit exhibit varied proteolytic activities and subcellular localization in vivo 2, 18. ![]() There are mainly two isoforms of presenilin, PS1/PS2, and three isoforms of APH-1, APH-1aL/aS/b, in human. A γ-secretase complex comprises APH-1, Pen-2, nicastrin and the catalytic subunit presenilin 16, 17. However, APP and Notch bind γ-secretase in a similar manner, complicating the design of substrate-selective γ-secretase inhibitors (GSIs) 14, 15.Ī strategy to differentially inhibit γ-secretase’ cleavage of different substrates is to target the distinct isoforms of its constituents. Selective inhibition of γ-secretase cleavage of APP over Notch has been proposed to mitigate the side effects. ![]() The side effects may be in part attributed to the nonspecific inhibition of γ-secretase’s cleavage of other substrates, especially Notch, which plays a crucial role in development and cell-fate determination 12, 13. However, this strategy has thus far failed to show benefits even worse, severe side effects were observed in clinical trials 10, 11. ![]() ![]() Inhibition of γ-secretase activity has been explored for AD treatment. Relatively longer Aβs tend to form oligomers and amyloid plaques in brain 6, 7, 8, 9.Īccumulation of amyloid plaques is a hallmark of AD. APP is initially cleaved by β-secretase to generate a carboxyl-terminal, 99 residue-containing fragment, known as APP-C99, which then undergoes sequential cleavages by γ-secretase, releasing the APP intracellular domain (AICD) and β-amyloid peptides (Aβ) in various lengths 5. The γ-secretase complex cleaves a variety of type I transmembrane (TM) proteins, exemplified by amyloid precursor protein (APP) and Notch 1, 2, 3, 4. ![]()
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