ReviewThe Journal of biological chemistry
Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?
Review 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 35 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
35 citing papers in PubMed, 54 citations in OpenAlex.
- The γ-secretase complex: from discovery to a therapeutic target.RSC chemical biology · 2026Review
- Article
- Functional relationships linking C99/APP-βCTF dimerization, proteostasis disruption, and organelle dysfunction.Cell communication and signaling : CCS · 2026Article
- A C. elegans model of familial Alzheimer's disease shows age-dependent synaptic degeneration independent of amyloid β-peptide.Neurobiology of disease · 2026Article
- Computer-aided Drug Design for Alzheimer's Disease: Recent Advancements and Future Perspectives.Current topics in medicinal chemistry · 2026Review
- Therapeutic and Diagnostic Roles of MSC-Derived Exosomes in Alzheimer's Disease.Brain and behavior · 2025Review
- Glycogen synthase kinase-3: the master switch driving neurodegeneration in Alzheimer's disease and Parkinson's disease.Archives of toxicology · 2025Review
- Characterization of endothelin-converting enzyme 1 as a key enzyme in the multienzyme Aβ degradation pathway.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- A Spectroscopic Study on the Amyloid-β Interaction with Clicked Peptide-Porphyrin Conjugates: a Vision Toward the Detection of Aβ Peptides in Aqueous Solution.Chembiochem : a European journal of chemical biology · 2024Article
- Mechanisms of autophagy-lysosome dysfunction in neurodegenerative diseases.Nature reviews. Molecular cell biology · 2024Review
- Autophagy-lysosomal-associated neuronal death in neurodegenerative disease.Acta neuropathologica · 2024Review
- γ-Secretase Modulator BPN15606 Reduced Aβ42 and Aβ40 and Countered Alzheimer-Related Pathologies in a Mouse Model of Down Syndrome.Annals of neurology · 2024Article
- Ectodomain shedding of PLA2R1 is mediated by the metalloproteases ADAM10 and ADAM17.The Journal of biological chemistry · 2024Article
- APP dyshomeostasis in the pathogenesis of Alzheimer's disease: implications for current drug targets.Alzheimer's research & therapy · 2024Review
- Increasing the Survival of a Neuronal Model of Alzheimer's Disease Using Docosahexaenoic Acid, Restoring Endolysosomal Functioning by Modifying the Interactions between the Membrane Proteins C99 and Rab5.International journal of molecular sciences · 2024Article
- siRNA drug delivery across the blood-brain barrier in Alzheimer's disease.Advanced drug delivery reviews · 2023Review
- Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by TyrScience advances · 2023Article
- Converging links between adult-onset neurodegenerative Alzheimer's disease and early life neurodegenerative neuronal ceroid lipofuscinosis?Neural regeneration research · 2023Review
- The Role of Mitochondrial Dysfunction in Alzheimer's: Molecular Defects and Mitophagy-Enhancing Approaches.Life (Basel, Switzerland) · 2023Review
- The η-secretase-derived APP fragment ηCTF is localized in Golgi, endosomes and extracellular vesicles and contributes to Aβ production.Cellular and molecular life sciences : CMLS · 2023Article
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Genetic, biochemical, and anatomical grounds led to the proposal of the amyloid cascade hypothesis centered on the accumulation of amyloid beta peptides (Aβ) to explain Alzheimer's disease (AD) etiology. In this context, a bulk of efforts have aimed at developing therapeutic strategies seeking to reduce Aβ levels, either by blocking its production (γ- and β-secretase inhibitors) or by neutralizing it once formed (Aβ-directed immunotherapies). However, so far the vast majority of, if not all, clinical trials based on these strategies have failed, since they have not been able to restore cognitive function in AD patients, and even in many cases, they have worsened the clinical picture. We here propose that AD could be more complex than a simple Aβ-linked pathology and discuss the possibility that a way to reconcile undoubted genetic evidences linking processing of APP to AD and a consistent failure of Aβ-based clinical trials could be to envision the pathological contribution of the direct precursor of Aβ, the β-secretase-derived C-terminal fragment of APP, βCTF, also referred to as C99. In this review, we summarize scientific evidences pointing to C99 as an early contributor to AD and postulate that γ-secretase should be considered as not only an Aβ-generating protease, but also a beneficial C99-inactivating enzyme. In that sense, we discuss the limitations of molecules targeting γ-secretase and propose alternative strategies seeking to reduce C99 levels by other means and notably by enhancing its lysosomal degradation.
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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 Socratic graph.