Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production

Topic: Brain proteins, microglia and lab models

Missense mutations in the amyloid precursor protein (APP) and presenilin-1 (PSEN1) cause early-onset familial Alzheimer’s disease (FAD) and alter proteolytic production of secreted 38-to-43-residue amyloid β-peptides (Aβ) by the PSEN1-containing γ-secretase complex, ostensibly supporting the amyloid hypothesis of pathogenesis. However, proteolysis of APP substrate by γ-secretase is processive, involving initial endoproteolysis to produce long Aβ 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 γ-secretase enzyme-substrate and/or enzyme-intermediate complexes. These stalled complexes triggered synaptic degeneration in a Caenorhabditis elegans model of FAD independently of Aβ production. Here, we conducted full quantitative analysis of all proteolytic events on APP substrate by γ-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 γ-secretase enzyme-substrate/intermediate complexes. The F386S mutation, however, does so only in Aβ-rich regions of the cells, not in C99-rich regions, consistent with the deficiencies of this mutant enzyme only in trimming of Aβ intermediates. These findings provide further evidence that FAD mutations lead to stalled and stabilized γ-secretase enzyme-substrate and/or enzyme-intermediate complexes and are consistent with the stalled process rather than the products of γ-secretase proteolysis as the pathogenic trigger.

@article{arafi2025-99d20e91,
  author  = {Arafi, Parnian and Devkota, Sujan and Williams, Emily L. and Maesako, Masato and Wolfe, Michael S.},
  title   = {{Alzheimer-mutant γ-secretase complexes stall amyloid β-peptide production}},
  journal = {eLife},
  year    = {2025},
  doi     = {10.7554/elife.102274.3},
  url     = {https://doi.org/10.7554/elife.102274.3}
}

Key findings

• 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 γ-secretase enzyme-substrate and/or enzyme-intermediate complexes.
• Fluorescence lifetime imaging microscopy in intact cells revealed that all six PSEN1 FAD mutations lead to stalled γ-secretase enzyme-substrate/intermediate complexes.
• These findings provide further evidence that FAD mutations lead to stalled and stabilized γ-secretase enzyme-substrate and/or enzyme-intermediate complexes and are consistent with the stalled process rather than the products of γ-secretase proteolysis as the pathogenic trigger.

Why it matters

This study found that six additional PSEN1 familial Alzheimer mutations cause deficiencies in multiple processing steps of APP by γ-secretase and lead to stalled enzyme-substrate or intermediate complexes. The results support the stalled complex hypothesis of familial Alzheimer's pathogenesis, but they are laboratory findings and do not demonstrate a treatment or cure.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.7554/elife.102274.3
• Original source →
• Free full text: eLife →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

Studies this one cites

Referenced by this study and also in the alzhub library, so you can read them here.

• APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases PLoS medicine · 2017-03-28 · usefulness score 64/100 · Risk genes beyond APOE
• γ-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer's disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS) The Lancet. Neurology · 2024-07-26 · usefulness score 63/100 · Risk genes beyond APOE
• The amyloid hypothesis of Alzheimer's disease at 25 years EMBO Molecular Medicine · 2016-03-29 · usefulness score 61/100 · Disease mechanisms
• Autosomal dominant and sporadic late onset Alzheimer's disease share a common in vivo pathophysiology Brain : a journal of neurology · 2022-10-01 · usefulness score 56/100 · Biomarkers
• Global, regional, and national burden of Alzheimer's disease and other dementias, 1990-2019 Frontiers in aging neuroscience · 2022-10-10 · usefulness score 56/100 · Caregiving
• Alzheimer's disease drug development pipeline: 2023 Alzheimer's & dementia (New York, N. Y.) · 2023-04-01 · usefulness score 53/100 · Mild cognitive impairment
• Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life Archives of neurology · 2005-12-01 · usefulness score 46/100 · Risk genes beyond APOE

Related studies in Risk genes beyond APOE

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• Selective intracellular release of copper and zinc ions from bis(thiosemicarbazonato) complexes reduces levels of Alzheimer disease amyloid-beta peptide The Journal of biological chemistry · 2007-12-17 · usefulness score 45/100
• Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice Nature medicine · 1997-01-01 · usefulness score 41/100
• Inhibitors of cathepsin B improve memory and reduce beta-amyloid in transgenic Alzheimer disease mice expressing the wild-type, but not the Swedish mutant, beta-secretase site of the amyloid precursor protein The Journal of biological chemistry · 2008-01-09 · usefulness score 44/100
• RAC1 inhibition targets amyloid precursor protein processing by gamma-secretase and decreases Abeta production in vitro and in vivo The Journal of biological chemistry · 2005-09-08 · usefulness score 41/100
• Making the final cut: pathogenic amyloid-β peptide generation by γ-secretase Cell stress · 2018-10-28 · usefulness score 45/100

Also tagged “precursor”

1,339 studies in the library carry the topic tag “precursor”; these are this study's neighbours in a fixed, alphabetical-by-hash tour of them, not the closest in content. All 1,339 tagged studies.

• Hippocampal atrophy and apolipoprotein E genotype are independently associated with Alzheimer's disease Annals of neurology · 1998-03-01 · usefulness score 47/100 · Hippocampus size on brain scans
• T cells specifically targeted to amyloid plaques enhance plaque clearance in a mouse model of Alzheimer's disease PloS one · 2010-05-26 · usefulness score 41/100 · TREM2 and immune genetics
• Generation and regulation of beta-amyloid peptide variants by neurons Journal of neurochemistry · 1998-11-01 · usefulness score 42/100 · Risk genes beyond APOE

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• Purification and cloning of amyloid precursor protein β-secretase from human brain 1999 · Disease mechanisms
• alpha- and beta-secretase: profound changes in Alzheimer's disease 2002 · Risk genes beyond APOE

More on Risk genes beyond APOE

• A review that covers this ground Amyloid β-peptide (1-42)-induced oxidative stress in Alzheimer disease: importance in disease pathogenesis and progression Antioxidants & redox signaling · 2013-02-14 · usefulness score 48/100
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See all studies in Risk genes beyond APOE →