Intracisternal delivery of NFκB-inducible scAAV2/9 reveals locoregional neuroinflammation induced by systemic kainic acid treatment.

Détails

Ressource 1Télécharger: BIB_648500CB71EC.P001.pdf (2559.69 [Ko])
Etat: Public
Version: de l'auteur⸱e
ID Serval
serval:BIB_648500CB71EC
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Intracisternal delivery of NFκB-inducible scAAV2/9 reveals locoregional neuroinflammation induced by systemic kainic acid treatment.
Périodique
Frontiers In Molecular Neuroscience
Auteur⸱e⸱s
Bockstael O., Tenenbaum L., Dalkara D., Melas C., De Witte O., Levivier M., Chtarto A.
ISSN
1662-5099 (Electronic)
ISSN-L
1662-5099
Statut éditorial
Publié
Date de publication
2014
Volume
7
Pages
92
Langue
anglais
Notes
Publication types: Journal ArticlePublication Status: epublish
Résumé
We have previously demonstrated disease-dependent gene delivery in the brain using an AAV vector responding to NFκB activation as a probe for inflammatory responses. This vector, injected focally in the parenchyma prior to a systemic kainic acid (KA) injection mediated inducible transgene expression in the hippocampus but not in the cerebellum, regions, respectively, known to be affected or not by the pathology. However, such a focal approach relies on previous knowledge of the model parameters and does not allow to predict the whole brain response to the disease. Global brain gene delivery would allow to predict the regional distribution of the pathology as well as to deliver therapeutic factors in all affected brain regions. We show that self-complementary AAV2/9 (scAAV2/9) delivery in the adult rat cisterna magna allows a widespread but not homogenous transduction of the brain. Indeed, superficial regions, i.e., cortex, hippocampus, and cerebellum were more efficiently transduced than deeper regions, such as striatum, and substantia nigra. These data suggest that viral particles penetration from the cerebrospinal fluid (CSF) into the brain is a limiting factor. Interestingly, AAV2/9-2YF a rationally designed capsid mutant (affecting surface tyrosines) increased gene transfer efficiency approximately fivefold. Neurons, astrocytes, and oligodendrocytes, but not microglia, were transduced in varying proportions depending on the brain region and the type of capsid. Finally, after a single intracisternal injection of scAAV2/9-2YF using the NFκB-inducible promoter, KA treatment induced transgene expression in the hippocampus and cortex but not in the cerebellum, corresponding to the expression of the CD11b marker of microglial activation. These data support the use of disease-inducible vectors administered in the cisterna magna as a tool to characterize the brain pathology in systemic drug-induced or transgenic disease models. However, further improvements are required to enhance viral particles penetration into the brain.
Pubmed
Web of science
Open Access
Oui
Création de la notice
13/02/2015 17:40
Dernière modification de la notice
20/08/2019 14:20
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