ArticleCNS neuroscience & therapeutics2013
The γ-secretase blocker DAPT reduces the permeability of the blood-brain barrier by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia.
Article in CNS neuroscience & therapeutics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 50 citations in OpenAlex.
- Modulating Th17/Treg Balance in Alzheimer's Disease: Therapeutic Insights from Natural Compounds and Immunometabolism.Brain sciences · 2026Review
- Tubuloside B ameliorates blood-brain barrier disruption and cognitive deficits after cerebral ischemia by inhibiting TRIC protein ubiquitination and degradation.Journal of neuroinflammation · 2025Article
- Microfluidic-Based Technologies for Crossing the Blood-Brain Barrier Against Alzheimer's Disease: Novel Strategies and Challenges.International journal of molecular sciences · 2025Review
- A Novel Perspective on PCSK9 in Alzheimer's Disease: A Focus on Amyloid Beta.Current medicinal chemistry · 2025Review
- Endothelial lincRNA-p21 alleviates cerebral ischemia/reperfusion injury by maintaining blood-brain barrier integrity.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2024Article
- An easy-to-perform method for microvessel isolation and primary brain endothelial cell culture to study Alzheimer's disease.Heliyon · 2024Article
- The Basic Requirement of Tight Junction Proteins in Blood-Brain Barrier Function and Their Role in Pathologies.International journal of molecular sciences · 2024Review
- A high throughput blood-brain barrier model incorporating shear stress with improved predictive power for drug discovery.Biomicrofluidics · 2023Article
- Blood-brain barrier dysfunction and Alzheimer's disease: associations, pathogenic mechanisms, and therapeutic potential.Frontiers in aging neuroscience · 2023Review
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- DAPT Attenuates Cadmium-Induced Toxicity in Mice by Inhibiting Inflammation and the Notch/HES-1 Signaling Axis.Frontiers in pharmacology · 2022Article
- Damage to the blood‑brain barrier and activation of neuroinflammation by focal cerebral ischemia under hyperglycemic condition.International journal of molecular medicine · 2021Article
- The Role of Ubiquitin-Proteasome Pathway and Autophagy-Lysosome Pathway in Cerebral Ischemia.Oxidative medicine and cellular longevity · 2020Review
- Preactivation of Notch1 in remote ischemic preconditioning reduces cerebral ischemia-reperfusion injury through crosstalk with the NF-κB pathway.Journal of neuroinflammation · 2019Article
- Activation of Notch signaling by soluble Dll4 decreases vascular permeability via a cAMP/PKA-dependent pathway.American journal of physiology. Heart and circulatory physiology · 2019Article
- Therapeutic Target and Cell-signal Communication of Chlorpromazine and Promethazine in Attenuating Blood-Brain Barrier Disruption after Ischemic Stroke.Cell transplantation · 2019Article
- The peripheral immune response after stroke-A double edge sword for blood-brain barrier integrity.CNS neuroscience & therapeutics · 2018Review
- The role of ubiquitination and deubiquitination in the regulation of cell junctions.Protein & cell · 2018Review
- Tempol Protects Against Acute Renal Injury by Regulating PI3K/Akt/mTOR and GSK3β Signaling Cascades and Afferent Arteriolar Activity.Kidney & blood pressure research · 2018Article
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundTight junction protein degradation is a principal characteristic of the blood-brain barrier (BBB) damage that occurs during brain ischemia.
aimsWe investigated the mechanisms of occludin degradation that underlie permanent middle cerebral artery occlusion (pMCAO) in rats. METHODS AND
resultsWestern blot and Co-immunoprecipitation data indicated ubiquitination and degradation of occludin in brain after pMCAO, which was consistent with ZO-1 degradation in penumbra regions as observed at 24 h after pMCAO. We further investigated candidate protease(s) responsible for the degradation of occludin during pMCAO. The intraventricular administration of γ-secretase blocker DAPT significantly inhibited the pMCAO-induced neurovascular damage, whereas ALLM and Batimastat, which are inhibitors of calpain and metalloproteinase proteases, respectively, were less effective. Notably, we found that DAPT significantly inhibited BBB disruption in comparison with vehicle treatment, as assessed by Evans blue excretion. Interestingly, the confocal immunostaining revealed that activation of the E3 ubiquitin ligase Itch is associated with degradation of occludin in brain microvessels following ischemia. Furthermore, our data demonstrate that the inhibition of γ-secretase signaling and the itch-mediated ubiquitination of occludin likely underlie the vasoprotective effect of DAPT after pMCAO.
conclusionThe γ-secretase blocker DAPT reduces the permeability of the BBB by decreasing the ubiquitination and degradation of occludin during permanent brain ischemia, suggesting that γ-secretase may represent a novel therapeutic target for preventing neurovascular damage.
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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.