Fig. 1
Mutations in PSEN1, PSEN2, and APP TMD cause ADAD with varying AAOs. A Schematic showing PSEN1 and PSEN2 isoforms, which share 66% homology. The colour gradient displays local homology between PSEN1 and PSEN2 (based on NCBI's Basic Local Alignment Search Tool (BLAST) using BLOSUM 62 matrix). B GSEC-APPC99 co-structure (PDB: 8X54). PSEN (purple) forms the catalytic subunit, while Nicastrin (yellow), PEN2 (green), and APH1 A/B (blue) are essential subunits of the GSEC complex. APPC99 is the direct substrate of GSEC (red). C Schematic representation of PSEN1- and PSEN2-type GSEC complex subcellular localizations. PSEN1-type GSEC complexes (red) are broadly distributed (both in the plasma membrane and in late endosomes), while PSEN2-type GSECs (in yellow) are restricted to late endosomes. Created in BioRender. Gutierrez Fernandez, S. (2025) https://BioRender.com/v47y310 D. APP cleavage by BACE1 generates APPC99, the direct GSEC substrate. The initial GSEC-mediated cut (endopeptidase activity) releases AICD50-99 or AICD49-99 and generates longer Aβ fragments (Aβ48 or Aβ49). These fragments undergo sequential γ-cleavages to produce Aβ peptides of various lengths. Pathogenic mutations destabilize the GSEC-APP/Aβ complex, reducing sequential cleavage efficiency (processivity) and increasing the release of longer, more toxic Aβ peptides. E Age at symptom onset (AAO) associated with mutations in PSEN1, PSEN2, and APP genes. PSEN1 harbours most ADAD mutations with broadly distributed AAOs (23 - 75y). PSEN2 and APP mutations are associated with later onsets (33 - 64y and 39 - 87y, respectively). Box plots show the median (centre line) and 25 - 75 percentiles. Dots represent individual mutations plotted as averaged mean ± SD. Data was sourced from Alzforum database (https://www.alzforum.org/mutations) and literature (see Supplementary Tables S1, S2 and S3)