ArticleThe Journal of biological chemistry2012
Generation of Alzheimer disease-associated amyloid β42/43 peptide by γ-secretase can be inhibited directly by modulation of membrane thickness.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 43 papers.
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Who cites it
43 citing papers in PubMed, 98 citations in OpenAlex.
- Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Effects of PF-06751979, a Potent and Selective Oral BACE1 Inhibitor: Results from Phase I Studies in Healthy Adults and Healthy Older Subjects.Journal of Alzheimer's disease : JAD · 2019Trial
- Mechanistic role of APOE lipidation in Alzheimer's disease pathogenesis.Theranostics · 2026Review
- A unique subpopulation of wild-type neurons recapitulating familial Alzheimer's disease phenotypes.Cell death & disease · 2025Article
- Cholesterol and Lipid Rafts in the Biogenesis of Amyloid-β Protein and Alzheimer's Disease.Annual review of biophysics · 2024Review
- Phospholipase Modulation of Synaptic Membrane Landscape: Driving Force Behind Memory Formation?Cold Spring Harbor perspectives in biology · 2024Review
- New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.The EMBO journal · 2024Review
- Towards a Unitary Hypothesis of Alzheimer's Disease Pathogenesis.Journal of Alzheimer's disease : JAD · 2024Article
- Lipid environment modulates processivity and kinetics of a presenilin homolog acting on multiple substrates in vitro.The Journal of biological chemistry · 2023Article
- Cholesterol-dependent amyloid β production: space for multifarious interactions between amyloid precursor protein, secretases, and cholesterol.Cell & bioscience · 2023Review
- Endosome and Lysosome Membrane Properties Functionally Link to γ-Secretase in Live/Intact Cells.Sensors (Basel, Switzerland) · 2023Article
- Formation of extramembraneProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Rhomboid-catalyzed intramembrane proteolysis requires hydrophobic matching with the surrounding lipid bilayer.Science advances · 2022Article
- Article
- Complement System in Alzheimer's Disease.International journal of molecular sciences · 2021Review
- Activity of Selected Group of Monoterpenes in Alzheimer's Disease Symptoms in Experimental Model Studies-A Non-Systematic Review.International journal of molecular sciences · 2021Review
- Microbiota-derived short chain fatty acids modulate microglia and promote Aβ plaque deposition.eLife · 2021Article
- Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer's Disease, Parkinson's Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis.Chemical reviews · 2021Review
- γ-Secretase Partitioning into Lipid Bilayers Remodels Membrane Microdomains after Direct Insertion.Langmuir : the ACS journal of surfaces and colloids · 2020Article
- Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress.Journal of Alzheimer's disease : JAD · 2019Review
- Structure of APP-C99Biochimica et biophysica acta. Biomembranes · 2018Article
Corrections and comments
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Authors and funding
6 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Pathogenic generation of amyloid β-peptide (Aβ) by sequential cleavage of β-amyloid precursor protein (APP) by β- and γ-secretases is widely believed to causally underlie Alzheimer disease (AD). β-Secretase initially cleaves APP thereby generating a membrane-bound APP C-terminal fragment, from which γ-secretase subsequently liberates 37-43-amino acid long Aβ species. Although the latter cleavages are intramembranous and although lipid alterations have been implicated in AD, little is known of how the γ-secretase-mediated release of the various Aβ species, in particular that of the pathogenic longer variants Aβ(42) and Aβ(43), is affected by the lipid environment. Using a cell-free system, we have directly and systematically investigated the activity of γ-secretase reconstituted in defined model membranes of different thicknesses. We found that bilayer thickness is a critical parameter affecting both total activity as well as cleavage specificity of γ-secretase. Whereas the generation of the pathogenic Aβ(42/43) species was markedly attenuated in thick membranes, that of the major and rather benign Aβ(40) species was enhanced. Moreover, the increased production of Aβ(42/43) by familial AD mutants of presenilin 1, the catalytic subunit of γ-secretase, could be substantially lowered in thick membranes. Our data demonstrate an effective modulation of γ-secretase activity by membrane thickness, which may provide an approach to lower the generation of the pathogenic Aβ(42/43) species.
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