In vivo/Ex Vivo EPR Investigation of the Brain Redox Status and Blood--Brain Barrier Integrity in the 5xFAD Mouse Model of Alzheimer's Disease.
2021
Аутори:
Vesković, AnaNakarada, Đura
Pavićević, Aleksandra
Prokić, Bogomir
Perović, Milka
Kanazir, Selma
Popović-Bijelić, Ana
Mojović, Miloš
Тип документа:
Чланак у часопису (Објављена верзија)
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© 2021 Bentham Science Publishers
Метаподаци
Приказ свих података о документуАпстракт:
BACKGROUND Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by cognitive decline and total brain atrophy. Despite the substantial scientific effort, the pathological mechanisms underlying neurodegeneration in AD are currently unknown. In most studies, amyloid β peptide has been considered the key pathological change in AD. However, numerous Aβ-targeting treatments have failed in clinical trials. This implies the need to shift the re- search focus from Aβ to other pathological features of the disease. OBJECTIVE The aim of this study was to examine the interplay between mitochondrial dysfunction, oxidative stress and blood-brain barrier (BBB) disruption in AD pathology, using a novel approach that involves the application of electron paramagnetic resonance (EPR) spectroscopy. METHOD In vivo and ex vivo EPR spectroscopy using two spin probes (aminoxyl radicals) exhibit- ing different cell-membrane and BBB permeability were employed to assess BBB integrity and brain tissue redox status in the 5xFAD mouse model of AD. In vivo spin probe reduction decay was analyzed using a two-compartment pharmacokinetic model. Furthermore, 15 K EPR spectros- copy was employed to investigate the brain metal content. RESULTS This study has revealed an altered brain redox state, BBB breakdown, as well as ROS-me- diated damage to mitochondrial iron-sulfur clusters, and up-regulation of MnSOD in the 5xFAD model. CONCLUSION The EPR spin probes were shown to be excellent in vivo reporters of the 5xFAD neu- ronal tissue redox state, as well as the BBB integrity, indicating the importance of in vivo EPR spec- troscopy application in preclinical studies of neurodegenerative diseases.
Кључне речи:
5xFAD.; Alzheimer’s disease; EPR; Blood-brain barrier; Mitochondria; Spin probesИзвор:
Current Alzheimer Research, 2021, 18, 1, 25-34Финансирање / пројекти:
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200007 (Универзитет у Београду, Институт за биолошка истраживања 'Синиша Станковић') (RS-MESTD-inst-2020-200007)
- Министарство науке, технолошког развоја и иновација Републике Србије, институционално финансирање - 200146 (Универзитет у Београду, Факултет за физичку хемију) (RS-MESTD-inst-2020-200146)
- PHYCAT - Protein Hydrogel for Cancer Theranostics (RS-ScienceFundRS-Promis-6062285)
DOI: 10.2174/1567205018666210324121156
ISSN: 1567-2050
PubMed: 33761860