ArticleThe Journal of cell biology2019
A cellular complex of BACE1 and γ-secretase sequentially generates Aβ from its full-length precursor.
Article in The Journal of cell biology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 63 citations in OpenAlex.
- Neuroinflammation and Secretase Regulation in Alzheimer's Disease: From Molecular Cross-Talk to Multi-Target Therapeutics.International journal of molecular sciences · 2026Review
- A new era in neuropharmacology: assessing the efficacy and safety of novel anti-amyloid and non-amyloid drug targets for Alzheimer's disease.Journal of neurology · 2026Review
- Is the Era of One-Size-Fits-All Alzheimer's Treatment Officially Over?Journal of molecular neuroscience : MN · 2025Review
- Endothelial delivery of simvastatin by LRP1-targeted nanoparticles ameliorates pathogenesis of alzheimer's disease in a mouse model.Alzheimer's research & therapy · 2025Article
- Selective Protonation of Catalytic Dyad for γ-Secretase-Mediated Hydrolysis Revealed by Multiscale Simulations.The journal of physical chemistry. B · 2024Article
- Exploring the Connection Between Nanomaterials and Neurodegenerative Disorders.Micromachines · 2024Review
- Rhei Undulati Rhizoma attenuates memory decline and reduces amyloid-β induced neuritic dystrophy in 5xFAD mouse.Chinese medicine · 2024Article
- Multicolor, Cell-Impermeable, and High Affinity BACE1 Inhibitor Probes Enable Superior Endogenous Staining and Imaging of Single Molecules.Journal of medicinal chemistry · 2024Article
- APP-BACE1 Interaction and Intracellular Localization Regulate Aβ Production in iPSC-Derived Cortical Neurons.Cellular and molecular neurobiology · 2023Article
- High throughput and targeted screens for prepilin peptidase inhibitors do not identify common inhibitors of eukaryotic gamma-secretase.Expert opinion on drug discovery · 2023Article
- The Amyloid Cascade Hypothesis in Alzheimer's Disease: Should We Change Our Thinking?Biomolecules · 2023Review
- The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer's Disease.International journal of molecular sciences · 2023Article
- Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2023Article
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- An ultra-sensitive immunoassay detects and quantifies soluble Aβ oligomers in human plasma.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2022Article
- Meprin β knockout reduces brain Aβ levels and rescues learning and memory impairments in the APP/lon mouse model for Alzheimer's disease.Cellular and molecular life sciences : CMLS · 2022Article
- Neurodegenerative Disorders of Alzheimer, Parkinsonism, Amyotrophic Lateral Sclerosis and Multiple Sclerosis: An Early Diagnostic Approach for Precision Treatment.Metabolic brain disease · 2022Review
- EDEM1 Regulates Amyloid Precursor Protein (APP) Metabolism and Amyloid-β Production.International journal of molecular sciences · 2021Article
- Intermittent hypoxia treatment alleviates memory impairment in the 6-month-old APPswe/PS1dE9 mice and reduces amyloid beta accumulation and inflammation in the brain.Alzheimer's research & therapy · 2021Article
- Nanoscale organization of Nicastrin, the substrate receptor of the γ-secretase complex, as independent molecular domains.Molecular brain · 2021Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
Intramembrane proteolysis of transmembrane substrates by the presenilin-γ-secretase complex is preceded and regulated by shedding of the substrate's ectodomain by α- or β-secretase. We asked whether β- and γ-secretases interact to mediate efficient sequential processing of APP, generating the amyloid β (Aβ) peptides that initiate Alzheimer's disease. We describe a hitherto unrecognized multiprotease complex containing active β- and γ-secretases. BACE1 coimmunoprecipitated and cofractionated with γ-secretase in cultured cells and in mouse and human brain. An endogenous high molecular weight (HMW) complex (∼5 MD) containing β- and γ-secretases and holo-APP was catalytically active in vitro and generated a full array of Aβ peptides, with physiological Aβ42/40 ratios. The isolated complex responded properly to γ-secretase modulators. Alzheimer's-causing mutations in presenilin altered the Aβ42/40 peptide ratio generated by the HMW β/γ-secretase complex indistinguishably from that observed in whole cells. Thus, Aβ is generated from holo-APP by a BACE1-γ-secretase complex that provides sequential, efficient RIP processing of full-length substrates to final products.
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Registered trials
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 OpenQuestion graph.