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  • Studies regarding secretase nowadays aim at

    2022-06-18

    Studies regarding γ-secretase nowadays aim at elucidating how APP is recognized and recruited. It has been suggested based on coarse-grained molecular simulation that the recognition and recruitment of substrate can occur on an extended surface covering PS1's TM2/6/9 domains and PAL motif [15]. Translocation of the substrate to the active site is likely coupled with a large-scale conformational change. Indeed, it was suggested that a considerable conformational change in nicastrin (NCT) extracellular domain is required in order to allow the accessibility of the active site of PS. In particular, the heavily glycosylated ECD of NCT is thought to recognize the substrate N-terminus [3] and redirect it to PS catalytic pocket for further cleavage processing. The cryo-EM structure at 3.4 Å of resolution (PDB: 5A63) does indeed provide density map for 10 out of 16 potential glycosylated sites [3]; however, it is not currently known the function of these N-linked glycans and further investigations are required. Recently, it was observed that the monomeric APP interacts with both NTF and CTF and the flexibility of the APP influences the stability of these interactions [15]. Moreover, the non-covalent APP homodimer is protected from cleavage of γ-secretase independently from the dimerization motif [16]. Therefore, in this study we investigated the interplay between APP and γ-secretase with particular attention to the specific membrane environment, namely, the effect of the lipids membrane composition. Several experimental evidences associate lipid rafts to APP amyloidogenic processing. In fact, the β-secretase and γ-secretase L-Glutathione Reduced as well as the full-length APP and the APP C-terminal fragments are localized in lipid raft domains [17], [18], [19], [20], whereas other substrates (e.g. Notch1, Jagged2 or N-cadherin) reside in non-raft membrane [18]. These results suggested that raft domains act as large platforms for proteins recruitment selecting amyloidogenic substrates. Therefore, based on lipidomics analysis of brain tissues, we modeled a realistic synaptic plasma membrane (SPM) [21], where L-Glutathione Reduced we monitored lipids raft formation. The γ-secretase complex surrounded by APP proteins was embedded in this SPM model and a coarse-grained (CG) approach [22], [23] was used in order to investigate the recruitment and recognition of the APP by γ-secretase along with the raft formation with respect to the proteins' localization. Our molecular simulations shed light on the complex mechanism of γ-secretase APP recruitment by modeling a realistic membrane environment and by providing essential information for the further study of γ-secretase binding and inhibition modes of action.
    Material and methods
    Results and discussion
    Conclusions During the last 20 years, our knowledge of the AD's neurobiology has increased tremendously leading to the development of several putative disease-modifying treatments. Particular attention was recently raised for the disease–modifying therapies based on the inhibition or modulation of α-, β- and γ-secretases [45], [46], [47], [48]. γ-secretase notably not only cleaves Aβ peptides but many other transmembrane proteins, for instance Notch protein. This broad range of substrates is therefore the main cause of toxicity in preclinical tests of existing γ-secretase inhibitors. Therefore, exhaustive efforts have been made to design more specific APP/γ-secretase modulators. For example, it was discovered that some small molecules [49] as well as non-steroidal anti-inflammatory drugs (NSAIDs) might modulate the APP cleavage without interfering with the cleavage of other substrates. This initial study shed light on the early stages of APP recruitment and interaction mechanism with γ-secretase, which would be important for further drug design investigations. Altogether, our results provide a glimpse on the proteolytic processes involved in AD pathology representing also a promising starting point for future investigations on the mechanism of γ-secretase inhibitors.