ArticleJournal of neurochemistry2011
Targets for AD treatment: conflicting messages from γ-secretase inhibitors.
Article in Journal of neurochemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers, 1 of them a synthesis that pooled it.
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The trial behind it
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
39 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.
- Dissecting Complex and Multifactorial Nature of Alzheimer's Disease Pathogenesis: a Clinical, Genomic, and Systems Biology Perspective.Molecular neurobiology · 2016Pooled it
- 5xFAD mutations induce hearing impairment in the Ahl-corrected 5xFAD mice.Experimental neurology · 2025Article
- Neuroprotective Strategies and Cell-Based Biomarkers for Manganese-Induced Toxicity in Human Neuroblastoma (SH-SY5Y) Cells.Biomolecules · 2024Article
- PED: a novel predictor-encoder-decoder model for Alzheimer drug molecular generation.Frontiers in artificial intelligence · 2024Article
- 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
- Based on molecular structures: Amyloid-β generation, clearance, toxicity and therapeutic strategies.Frontiers in molecular neuroscience · 2022Review
- Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer's Disease.Pharmaceutics · 2021Article
- Computational Evaluation of Interaction Between Curcumin Derivatives and Amyloid-β Monomers and Fibrils: Relevance to Alzheimer's Disease.Journal of Alzheimer's disease : JAD · 2021Article
- Galectin 3-binding protein suppresses amyloid-β production by modulating β-cleavage of amyloid precursor protein.The Journal of biological chemistry · 2020Article
- Translational inhibition of APP by Posiphen: Efficacy, pharmacodynamics, and pharmacokinetics in the APP/PS1 mouse.Alzheimer's & dementia (New York, N. Y.) · 2018Article
- Adiponectin controls the apoptosis and the expression of tight junction proteins in brain endothelial cells through AdipoR1 under beta amyloid toxicity.Cell death & disease · 2017Article
- Evaluation of Renal Function in Alzheimer's Disease and Geriatric Patients: Results from a Turkish Two-center Study.Journal of medical biochemistry · 2017Article
- Targeting protein aggregation for the treatment of degenerative diseases.Nature reviews. Drug discovery · 2015Review
- Polyphenols as therapeutic molecules in Alzheimer's disease through modulating amyloid pathways.Molecular neurobiology · 2015Review
- Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer's disease.Current Alzheimer research · 2015Article
- Evidence for lymphatic Aβ clearance in Alzheimer's transgenic mice.Neurobiology of disease · 2014Article
- Lessons from a BACE1 inhibitor trial: off-site but not off base.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2014Article
- Evidence of a novel mechanism for partial γ-secretase inhibition induced paradoxical increase in secreted amyloid β protein.PloS one · 2014Article
- Identification of microRNAs involved in Alzheimer's progression using a rabbit model of the disease.American journal of neurodegenerative disease · 2014Article
- Major carboxyl terminal fragments generated by γ-secretase processing of the Alzheimer amyloid precursor are 50 and 51 amino acids long.The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry · 2013Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 1 country.
Funding
Abstract
Current evidence suggests that Alzheimer's disease (AD) is a multi-factorial disease that starts with accumulation of multiple proteins. We have previously proposed that inhibition of γ-secretase may impair membrane recycling causing neurodegeneration starting at synapses (Sambamurti K., Suram A., Venugopal C., Prakasam A., Zhou Y., Lahiri D. K. and Greig N. H. A partial failure of membrane protein turnover may cause Alzheimer's disease: a new hypothesis. Curr. Alzheimer Res., 3, 2006, 81). We also proposed familal AD mutations increase Aβ42 by inhibiting γ-secretase. Herein, we discuss the failure of Eli Lilly's γ-secretase inhibitor, semagacestat, in clinical trials in the light of our hypothesis, which extends the problem beyond toxicity of Aβ aggregates. We elaborate that γ-secretase inhibitors lead to accumulation of amyloid precursor protein C-terminal fragments that can later be processed by γ-secretase to yields bursts of Aβ to facilitate aggregation. Although we do not exclude a role for toxic Aβ aggregates, inhibition of γ-secretase can affect numerous substrates other than amyloid precursor protein to affect multiple pathways and the combined accumulation of multiple peptides in the membrane may impair its function and turnover. Taken together, protein processing and turnover pathways play an important role in maintaining cellular homeostasis and unless we clearly see consistent disease-related increase in their levels or activity, we need to focus on preserving their function rather than inhibiting them for treatment of AD and similar diseases.
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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.