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However, proteolysis of APP substrate by \u03b3-secretase is processive, involving initial endoproteolysis to produce long A\u03b2 peptides of 48 or 49 residues followed by carboxypeptidase trimming in mostly tripeptide increments. We recently reported evidence that FAD mutations in APP and PSEN1 cause deficiencies in early steps in processive proteolysis of APP substrate C99 and that this results from stalled \u03b3-secretase enzyme-substrate and\/or enzyme-intermediate complexes. These stalled complexes triggered synaptic degeneration in a\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    model of FAD independently of A\u03b2 production. Here, we conducted full quantitative analysis of all proteolytic events on APP substrate by \u03b3-secretase with six additional PSEN1 FAD mutations and found that all six are deficient in multiple processing steps. However, only one of these (F386S) was deficient in certain trimming steps but not in endoproteolysis. Fluorescence lifetime imaging microscopy in intact cells revealed that all six PSEN1 FAD mutations lead to stalled \u03b3-secretase enzyme-substrate\/intermediate complexes. The F386S mutation, however, does so only in A\u03b2-rich regions of the cells, not in C99-rich regions, consistent with the deficiencies of this mutant enzyme only in trimming of A\u03b2 intermediates. These findings provide further evidence that FAD mutations lead to stalled and stabilized \u03b3-secretase enzyme-substrate and\/or enzyme-intermediate complexes and are consistent with the stalled process rather than the products of \u03b3-secretase proteolysis as the pathogenic trigger.\n                  <\/jats:p>","DOI":"10.7554\/elife.102274","type":"journal-article","created":{"date-parts":[[2024,11,26]],"date-time":"2024-11-26T10:59:02Z","timestamp":1732618742000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.102274","source":"Crossref","is-referenced-by-count":7,"title":["Alzheimer-mutant \u03b3-secretase complexes stall amyloid \u03b2-peptide production"],"prefix":"10.7554","volume":"13","author":[{"given":"Parnian","family":"Arafi","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/001tmjg57","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Medicinal Chemistry, University of Kansas","place":["Lawrence, United 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