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  • br Conclusion and future directions

    2022-01-21


    Conclusion and future directions GS is an important therapeutic target for the treatment of Alzheimer's disease. Its structure and function have been studied during the last years to understand the substrate cleavage mechanism to modulate the Aβ42 peptide production. The recent elucidation of GS structures by cryo-EM has opened a new field for its study through computational approaches. Currently, there are only a few MD simulation studies that attempt to explore the mechanism of substrate recognition, identify the substrate entry site, and the transition between active/inactive states of the catalytic component (i.e. PS1). However, further studies are needed to understand (1) the importance of the physical chemistry environment (e.g. temperature, bilayer lipid composition, pH) in the integrity and activity of the GS complex [[51], [52], [53]], (2) the effect of mutations causing early-onset familial Alzheimer's disease (FAD) [54], and (3) the mechanism of GS inhibition/modulation of external agents (e.g. DAPT) [55]. Addressing these issues will allow us to go one step further into the dynamic characterization of the GS complex and the rational design of new drugs for the treatment of Alzheimer's disease.
    Conflict of interest
    Acknowledgments R. Aguayo-Ortiz (No. 510728/288862) is grateful to CONACyT for the fellowship granted. LD gratefully acknowledge the support of the Programa de Apoyo a la Investigación y el Posgrado (PAIP 5000-9155) and Programa de Apoyo a Proyectos de Investigación e Innovación Tecnológica (PAPIIT IA204716).
    Introduction The γ-secretase complex is a membrane protease involved in the proteolytic cleavage of a range of substrates (1, 2, 3), including the amyloid precursor protein (APP) and the Notch protein (2). Amyloidogenic APP cleavages by β- and γ-secretases generate amyloid β (Aβ) peptides, which oligomerize and form the Aβ plaques leading to Alzheimer's disease (AD) pathology (1). Because of this Caspase-2, human recombinant proteinase pathogenic effect, γ-secretase has been a target for the development of drugs against AD (4). The γ-secretase complex is composed of four subunits/proteins: presenilin-1 (PS1) (5), nicastrin (NCT), anterior pharynx defective 1 (APH-1), and presenilin enhancer 2 (PEN-2) (6, 7) (Fig. 1, A and B). PS1 serves as the catalytic core (8, 9, 10). Fig. 1 C displays the catalytic residues Asp257 and Asp385, along with the nearby residues (Met146, Trp165, Met233, and Gly384) that coordinate the inhibitor, DAPT, observed in cryo-electron microscopy (11). Cleavage of substrate (99 residue C-terminal fragment of the APP) by PS1 proceeds in two steps (12): ε-cleavage (endopeptidase activity), followed by γ-cleavage (carboxypeptidase activity) to release the Aβ peptide to the extracellular (EC) medium. PS1 is composed of nine transmembrane (TM) helices, TM1–TM9 (Fig. 1 C). Many mutations implicated in the formation of Aβ, including 90% of familial AD mutations, are located in PS1 (2, 13, 14, 15, 16). NCT forms the EC domain, except for its C-terminal helix, which inserts into the membrane. It is composed of two lobes, large and small (LL and SL). Glu333 near the interlobe interface, and the nearby DYIGS motif D336–S340, have been pointed out to be involved in substrate binding (17, 18, 19) (Fig. 1 B). PEN-2 helps stabilize the complex (20). APH-1 has seven TM helices; it plays an essential role in Notch signaling and aids in the assembly of premature components (21). Targeting Caspase-2, human recombinant proteinase γ-secretase for AD therapy requires the development of a compound that would inhibit the production of Aβ (especially Aβ42), which can also maintain the interactions with other substrates (2). Although a number of γ-secretase inhibitors have been developed and tested in humans with both AD and cancer, harmful side effects associated with blocking the Notch signaling pathway have been reported (2, 22). This motivated the development of γ-secretase modulators (GSMs) for the treatment of AD (23). Earlier studies have also pointed to the roles of γ-secretase-associated proteins (24), and to allosteric sites located within PS1 (25, 26, 27). Clinical trials have been initiated for a GSM, E2012, which reduces the production of Aβ without interfering with Notch signaling (23, 28).