ArticleThe Journal of biological chemistry
The C99 domain of the amyloid precursor protein resides in the disordered membrane phase.
Article in The Journal of biological chemistry. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed, 24 citations in OpenAlex.
- Article
- Increase of brain Aβ peptides and secretase activity during normal aging in rodent and human.GeroScience · 2026Article
- Are Hippocampal Hypoperfusion and ATP Depletion Prime Movers in the Genesis of Alzheimer's Disease? A Review of Recent Pertinent Observations from Molecular Biology.International journal of molecular sciences · 2025Review
- Developmental deletion of amyloid precursor protein precludes transcriptional and proteomic responses to brain injury.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025Article
- Microglial activation states and their implications for Alzheimer's Disease.The journal of prevention of Alzheimer's disease · 2025Review
- Advances in the cell biology of the trafficking and processing of amyloid precursor protein: impact of familial Alzheimer's disease mutations.The Biochemical journal · 2024Review
- The duality of amyloid-β: its role in normal and Alzheimer's disease states.Molecular brain · 2024Review
- Cholesterol and Lipid Rafts in the Biogenesis of Amyloid-β Protein and Alzheimer's Disease.Annual review of biophysics · 2024Review
- Nanodisc Reconstitution and Characterization of Amyloid-β Precursor Protein C99.Analytical chemistry · 2024Article
- Nanodisc reconstitution and characterization of amyloid-β precursor protein C99.bioRxiv : the preprint server for biology · 2024Article
- Lipid Peroxidation Drives Liquid-Liquid Phase Separation and Disrupts Raft Protein Partitioning in Biological Membranes.Journal of the American Chemical Society · 2024Article
- Saponin components inFrontiers in pharmacology · 2024Review
- Characterizing the transmembrane domains of ADAM10 and BACE1 and the impact of membrane composition.Biophysical journal · 2023Article
- Efficient calculation of the free energy for protein partitioning using restraining potentials.Biophysical journal · 2023Article
- Formation of extramembraneProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Immunotherapies for Alzheimer's Disease-A Review.Vaccines · 2022Review
- Interleukin-17A in Alzheimer's Disease: Recent Advances and Controversies.Current neuropharmacology · 2022Review
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
Processing of the amyloid precursor protein (APP) via the amyloidogenic pathway is associated with the etiology of Alzheimer's disease. The cleavage of APP by β-secretase to generate the transmembrane 99-residue C-terminal fragment (C99) and subsequent processing of C99 by γ-secretase to yield amyloid-β (Aβ) peptides are essential steps in this pathway. Biochemical evidence suggests that amyloidogenic processing of C99 occurs in cholesterol- and sphingolipid-enriched liquid-ordered phase membrane rafts. However, direct evidence that C99 preferentially associates with these rafts has remained elusive. Here, we tested this by quantifying the affinity of C99-GFP for raft domains in cell-derived giant plasma membrane vesicles (GPMVs). We found that C99 was essentially excluded from ordered domains in vesicles from HeLa cells, undifferentiated SH-SY5Y cells, or SH-SY5Y-derived neurons; instead, ∼90% of C99 partitioned into disordered domains. The strong association of C99 with disordered domains occurred independently of its cholesterol-binding activity or homodimerization, or of the presence of the familial Alzheimer disease Arctic mutation (APP E693G). Finally, through biochemical studies we confirmed previous results, which showed that C99 is processed in the plasma membrane by α-secretase, in addition to the well-known γ-secretase. These findings suggest that C99 itself lacks an intrinsic affinity for raft domains, implying that either i) amyloidogenic processing of the protein occurs in disordered regions of the membrane, ii) processing involves a marginal subpopulation of C99 found in rafts, or iii) as-yet-unidentified protein-protein interactions with C99 in living cells drive this protein into membrane rafts to promote its cleavage therein.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.