ArticleCell death & disease2012
Coordination between proteasome impairment and caspase activation leading to TAU pathology: neuroprotection by cAMP.
Article in Cell death & disease, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
21 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.
- The proteasome as a druggable target with multiple therapeutic potentialities: Cutting and non-cutting edges.Pharmacology & therapeutics · 2020Pooled it
- Boosting Brain Clean-Up: Can Targeting UPS Genes Offer Neuroprotection?Molecular neurobiology · 2025Review
- Autophagy and Tau Protein.International journal of molecular sciences · 2021Review
- PACAP27 mitigates an age-dependent hippocampal vulnerability to PGJ2-induced spatial learning deficits and neuroinflammation in mice.Brain and behavior · 2020Article
- The activation of the chymotrypsin-like activity of the proteasome is regulated by soluble adenyl cyclase/cAMP/protein kinase A pathway and required for human sperm capacitation.Molecular human reproduction · 2019Article
- gH625-liposomes as tool for pituitary adenylate cyclase-activating polypeptide brain delivery.Scientific reports · 2019Article
- Mitochondrial and calcium perturbations in rat CNS neurons induce calpain-cleavage of Parkin: Phosphatase inhibition stabilizes pSerBiochimica et biophysica acta. Molecular basis of disease · 2019Article
- Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology.Molecular neurodegeneration · 2018Article
- Prostaglandin J2 promotes O-GlcNAcylation raising APP processing by α- and β-secretases: relevance to Alzheimer's disease.Neurobiology of aging · 2018Article
- Neurotoxic mechanisms by which the USP14 inhibitor IU1 depletes ubiquitinated proteins and Tau in rat cerebral cortical neurons: Relevance to Alzheimer's disease.Biochimica et biophysica acta. Molecular basis of disease · 2017Article
- The Proteasome and Oxidative Stress in Alzheimer's Disease.Antioxidants & redox signaling · 2016Review
- The Ubiquitin-Proteasome System: Potential Therapeutic Targets for Alzheimer's Disease and Spinal Cord Injury.Frontiers in molecular neuroscience · 2016Review
- Prostaglandin J2: a potential target for halting inflammation-induced neurodegeneration.Annals of the New York Academy of Sciences · 2016Review
- Tau-driven 26S proteasome impairment and cognitive dysfunction can be prevented early in disease by activating cAMP-PKA signaling.Nature medicine · 2016Article
- The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration.Aging cell · 2015Review
- Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies.Experimental & molecular medicine · 2015Review
- PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2.Biochimica et biophysica acta · 2014Article
- Extended ubiquitin species are protein-based DUB inhibitors.Nature chemical biology · 2014Article
- Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration.Frontiers in molecular neuroscience · 2014Review
- Tau clearance mechanisms and their possible role in the pathogenesis of Alzheimer disease.Frontiers in neurology · 2013Review
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Neurofibrillary tangles (NFTs) are hallmarks of Alzheimer's disease (AD). The main component of NFTs is TAU, a highly soluble microtubule-associated protein. However, when TAU is cleaved at Asp421 by caspases it becomes prone to aggregation leading to NFTs. What triggers caspase activation resulting in TAU cleavage remains unclear. We investigated in rat cortical neurons a potential coordination between proteasome impairment and caspase activation. We demonstrate that upon proteasome inhibition, the early accumulation of detergent-soluble ubiquitinated (SUb) proteins paves the way to caspase activation and TAU pathology. This occurs with two drugs that inhibit the proteasome by different means: the product of inflammation prostaglandin J2 (PGJ2) and epoxomicin. Our results pinpoint a critical early event, that is, the buildup of SUb proteins that contributes to caspase activation, TAU cleavage, TAU/Ub-protein aggregation and neuronal death. Furthermore, to our knowledge, we are the first to demonstrate that elevating cAMP in neurons with dibutyryl-cAMP (db-cAMP) or the lipophilic peptide PACAP27 prevents/diminishes caspase activation, TAU cleavage and neuronal death induced by PGJ2, as long as these PGJ2-induced changes are moderate. db-cAMP also stimulated proteasomes, and mitigated proteasome inhibition induced by PGJ2. We propose that targeting cAMP/PKA to boost proteasome activity in a sustainable manner could offer an effective approach to avoid early accumulation of SUb proteins and later caspase activation, and TAU cleavage, possibly preventing/delaying AD neurodegeneration.
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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.